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Dysregulation of BDNF in prefrontal cortex in Alzheimer’s diseaseToby Aarons1, Steven Bradburn1, Andrew Robinson2, Antony Payton3, Neil Pendleton2, Chris Murgatroyd1*1 Bioscience Research Centre, Manchester Metropolitan University, Manchester, United Kingdom2 Faculty of Biology, Medicine and Health,?School of Biological Sciences, Division of Neuroscience & Experimental Psychology,?University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.3Division of Informatics, Imaging & Data Sciences, School of Health Sciences, The University of Manchester* Dr Chris Murgatroyd, Bioscience Research Centre, Manchester Metropolitan University, Chester Street, Manchester, United Kingdom, M1 5GD. Tel: (+44)1612471212. E-mail: c.murgatroyd@mmu.ac.uk.Running title: BDNF regulation in ageing and Alzheimer’s diseaseAbstract Background: Brain-derived neurotrophic factor (BDNF) is essential for neurogenesis and has been implicated in Alzheimer’s disease (AD). However, few studies have investigated together the epigenetic, transcriptional and translational regulation of this peptide in the brain in relation to AD. Objective: To investigate mechanisms underlying how BDNF is possibly dysregulated in the brain in relation to ageing and AD neuropathology.Methods: Prefrontal cortex tissues were acquired from the Manchester Brain Bank (N = 67). BDNF exon I, and exon IV-containing transcripts and total long 3’ transcript gene expression were determined by quantitative PCR and bisulfite pyrosequencing was used to quantify DNA methylation within promoters I and IV. Protein concentrations were quantified via ELISA. Results: BDNF exon IV and total long 3’ isoform gene expression levels negatively associated with donor’s age at death (IV: r = -0.291, P = 0.020; total: r = -0.354, P = 0.004). Expression of BDNF exon I- containing isoform was significantly higher in Met-carriers of the rs6265 variant, compared to Val-homozygotes, when accounting for donor ages (F = 6.455, P = 0.014). BDNF total long 3’ transcript expression was significantly lower in those with early AD neuropathology, compared to those without any neuropathology (P = 0.021). There were no associations between BDNF promoter I and IV methylation or protein levels with ages, rs6265 genotype or AD neuropathology status.Conclusion: Prefrontal cortex BDNF gene expression is associated with ageing, rs6265 carrier status and AD neuropathology in a variant-specific manner that seems to be independent of DNA methylation influences. Key words: BDNF, DNA methylation, Alzheimer’s disease, prefrontal cortexIntroductionBrain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neurogenesis, synaptic plasticity and long-term potentiation (LTP) in the CNS ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0036-8075", "PMID" : "7886457", "abstract" : "The neurotrophins are signaling factors important for the differentiation and survival of distinct neuronal populations during development. To test whether the neurotrophins also function in the mature nervous system, the effects of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophic factor 3 (NT-3) on the strength of synaptic transmission in hippocampal slices were determined. Application of BDNF or NT-3 produced a dramatic and sustained (2 to 3 hours) enhancement of synaptic strength at the Schaffer collateral-CA1 synapses; NGF was without significant effect. The enhancement was blocked by K252a, an inhibitor of receptor tyrosine kinases. BDNF and NT-3 decreased paired-pulse facilitation, which is consistent with a possible presynaptic modification. Long-term potentiation could still be elicited in slices previously potentiated by exposure to the neurotrophic factors, which implies that these two forms of plasticity may use at least partially independent cellular mechanisms.", "author" : [ { "dropping-particle" : "", "family" : "Kang", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schuman", "given" : "E M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science (New York, N.Y.)", "id" : "ITEM-1", "issue" : "5204", "issued" : { "date-parts" : [ [ "1995", "3", "17" ] ] }, "page" : "1658-62", "title" : "Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus.", "type" : "article-journal", "volume" : "267" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/381706a0", "ISSN" : "0028-0836", "PMID" : "8649517", "abstract" : "Neurotrophins promote neuronal survival and differentiation, but the fact that their expression is modified by neuronal activity, suggests a role in regulating synapse development and plasticity. In developing hippocampus, the expression of brain derived neurotrophic factor (BDNF) and its receptor TrkB increases in parallel with the ability to undergo long-term potentiation (LTP). Here we report a mechanism by which BDNF modulates hippocampal LTP. Exogenous BDNF promoted the induction of LTP by tetanic stimulation in young (postnatal day 12-13) hippocampal slices, which in the absence of BDNF show only short-term potentiation (STP). This effect was due to an enhanced ability of hippocampal synapses to respond to tetanic stimulation, rather than to a direct modulation of the LTP-triggering mechanism. A TrkB-IgG fusion protein, which scavenges endogenous BDNF, reduced the synaptic responses to tetanus as well as the magnitude of LTP in adult hippocampus. Our results suggest that BDNF may regulate LTP in developing and adult hippocampus by enhancing synaptic responses to tetanic stimulation.", "author" : [ { "dropping-particle" : "", "family" : "Figurov", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pozzo-Miller", "given" : "Lucas D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olafsson", "given" : "Petur", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Ti", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Bai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-2", "issue" : "6584", "issued" : { "date-parts" : [ [ "1996", "6", "20" ] ] }, "page" : "706-709", "title" : "Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus", "type" : "article-journal", "volume" : "381" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[1,2]", "plainTextFormattedCitation" : "[1,2]", "previouslyFormattedCitation" : "[1,2]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[1,2]. BDNF has been implicated in the ‘age-by-disease hypothesis’, in which BDNF expression is reduced in the ageing brain and a reduction in BDNF expression has been associated with multiple neurological disorders ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/npp.2015.107", "ISSN" : "0893-133X", "PMID" : "25881116", "abstract" : "Expression of brain-derived neurotrophic factor (BDNF) and somatostatin (SST) mRNAs in the brain decreases progressively and robustly with age, and lower BDNF and SST expression in the brain has been observed in many brain disorders. BDNF is known to regulate SST expression; however, the mechanisms underlying decreased expression of both genes are not understood. DNA methylation (DNAm) is an attractive candidate mechanism. To investigate the contribution of DNAm to the age-related decline in BDNF and SST expression, the Illumina Infinium HumanMethylation450 Beadchip Array was used to quantify DNAm of BDNF (26 CpG loci) and SST (9 CpG loci) in the orbital frontal cortices of postmortem brains from 22 younger (age <42 years) and 22 older individuals (age >60 years) with known age-dependent BDNF and SST expression differences. Relative to the younger individuals, 10 of the 26 CpG loci in BDNF and 8 of the 9 CpG loci in SST were significantly hypermethylated in the older individuals. DNAm in BDNF exons/promoters I, II, and IV negatively correlated with BDNF expression (r=-0.37, p<0.05; r=-0.40, p<0.05; r=-0.24, p=0.07), and DNAm in SST 5' UTR and first exon/intron negatively correlated with SST expression (r=-0.48, p<0.01; r=-0.63, p<0.001), respectively. An expanded set of BDNF- and GABA-related genes exhibited similar age-related changes in DNAm and correlation with gene expression. These results suggest that DNAm may be a proximal mechanism for decreased expression of BDNF, SST, and other BDNF- and GABA-related genes with brain aging and, by extension, for brain disorders in which their expression is decreased.", "author" : [ { "dropping-particle" : "", "family" : "McKinney", "given" : "Brandon C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lin", "given" : "Chien-Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oh", "given" : "Hyunjung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tseng", "given" : "George C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lewis", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibille", "given" : "Etienne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychopharmacology", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2015", "10", "16" ] ] }, "page" : "2604-2613", "title" : "Hypermethylation of BDNF and SST Genes in the Orbital Frontal Cortex of Older Individuals: A Putative Mechanism for Declining Gene Expression with Age", "type" : "article-journal", "volume" : "40" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[3]", "plainTextFormattedCitation" : "[3]", "previouslyFormattedCitation" : "[3]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[3].Reductions in BDNF have been widely investigated as a mediator of age-associated decline in synaptic density and cognitive function ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/978-3-642-45106-5_9", "author" : [ { "dropping-particle" : "", "family" : "Lu", "given" : "B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nagappan", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "223-250", "title" : "BDNF and Synaptic Plasticity, Cognitive Function, and Dysfunction", "type" : "chapter" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[4]", "plainTextFormattedCitation" : "[4]", "previouslyFormattedCitation" : "[4]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[4], with a significant association between BDNF and cognitive ageing being observed ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.nlm.2008.07.014", "ISSN" : "1095-9564", "PMID" : "18707012", "abstract" : "Brain-derived neurotrophic factor (BDNF) is one of the key molecules modulating brain plasticity. While low circulating levels of BDNF have been suggested to predispose to Alzheimer's disease, very little data are available on its association with cognitive function in general population. We evaluated the association between plasma BDNF levels and cognition in a representative population sample of ageing men and women. The subjects (n=1389) were participants of the Dose-Responses to Exercise Training (DR's EXTRA) Study and represent a random sample of Eastern Finnish people (684 men and 705 women), 57-79 years of age at baseline of the study. Plasma BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA). Cognitive function was evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery. Women had a higher mean (+/-SEM) plasma BDNF level than men (1721+/-55vs. 1495+/-54pg/ml, P<0.001). In women, 1 SD decrease in BDNF increased the risk for a low score in Naming Test by 53% (95% CI 1.21-1.92, P<0.001), in Mini-Mental State Examination by 63% (95% CI 1.21-2.20, P=0.001), in Word List Memory by 56% (95% CI 1.08-2.26, P=0.019), in Word List Recall by 50% (95% CI 1.10-2.05, P=0.010), in Word List Saving by 49% (95% CI 1.12-1.99, P=0.007), and in Word List Recognition by 64% (95% CI 1.19-2.25, P=0.002). Data were adjusted for age, education, depression, impaired glucose metabolism, cardiovascular disease, antihypertensive medication, lipid lowering medication, use of sex hormones, smoking, alcohol consumption, storing time of plasma in the freezer and platelet count. BDNF was not associated with cognition in men. Present data suggest that plasma BDNF is a biomarker of impaired memory and general cognitive function in ageing women.", "author" : [ { "dropping-particle" : "", "family" : "Komulainen", "given" : "Pirjo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pedersen", "given" : "Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "H\u00e4nninen", "given" : "Tuomo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruunsgaard", "given" : "Helle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lakka", "given" : "Timo A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kivipelto", "given" : "Miia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hassinen", "given" : "Maija", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rauramaa", "given" : "Tuomas H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pedersen", "given" : "Bente K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rauramaa", "given" : "Rainer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurobiology of learning and memory", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "11" ] ] }, "page" : "596-603", "title" : "BDNF is a novel marker of cognitive function in ageing women: the DR's EXTRA Study.", "type" : "article-journal", "volume" : "90" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1523/JNEUROSCI.6251-09.2010", "ISSN" : "0270-6474", "PMID" : "20392958", "abstract" : "Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain-derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age, and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood.", "author" : [ { "dropping-particle" : "", "family" : "Erickson", "given" : "K. I.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prakash", "given" : "R. S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Voss", "given" : "M. W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaddock", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heo", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McLaren", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pence", "given" : "B. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "S. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vieira", "given" : "V. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Woods", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McAuley", "given" : "E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kramer", "given" : "A. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neuroscience", "id" : "ITEM-2", "issue" : "15", "issued" : { "date-parts" : [ [ "2010", "4", "14" ] ] }, "page" : "5368-5375", "title" : "Brain-Derived Neurotrophic Factor Is Associated with Age-Related Decline in Hippocampal Volume", "type" : "article-journal", "volume" : "30" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1038/npp.2016.126", "ISSN" : "0893-133X", "author" : [ { "dropping-particle" : "", "family" : "Oh", "given" : "Hyunjung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lewis", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibille", "given" : "Etienne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychopharmacology", "id" : "ITEM-3", "issue" : "13", "issued" : { "date-parts" : [ [ "2016", "12", "15" ] ] }, "page" : "3080-3091", "title" : "The Role of BDNF in Age-Dependent Changes of Excitatory and Inhibitory Synaptic Markers in the Human Prefrontal Cortex", "type" : "article-journal", "volume" : "41" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[5\u20137]", "plainTextFormattedCitation" : "[5\u20137]", "previouslyFormattedCitation" : "[5\u20137]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[5–7]. However, the underlying mechanisms behind age-associated BDNF declines are not completely understood.The human BDNF gene has a complex structure involving 9 promoters and 11 exons of which only the exon IX at the 5’ end contains the coding sequence ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ygeno.2007.05.004", "ISSN" : "0888-7543", "PMID" : "17629449", "abstract" : "Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has central roles in the development, physiology, and pathology of the nervous system. We have elucidated the structure of the human BDNF gene, identified alternative transcripts, and studied their expression in adult human tissues and brain regions. In addition, the transcription initiation sites for human BDNF transcripts were determined and the activities of BDNF promoters were analyzed in transient overexpression assays. Our results show that the human BDNF gene has 11 exons and nine functional promoters that are used tissue and brain-region specifically. Furthermore, noncoding natural antisense RNAs that display complex splicing and expression patterns are transcribed in the BDNF gene locus from the antiBDNF gene (approved gene symbol BDNFOS). We show that BDNF and antiBDNF transcripts form dsRNA duplexes in the brain in vivo, suggesting an important role for antiBDNF in regulating BDNF expression in human.", "author" : [ { "dropping-particle" : "", "family" : "Pruunsild", "given" : "Priit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kazantseva", "given" : "Anna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aid", "given" : "Tamara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Palm", "given" : "Kaia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Timmusk", "given" : "T\u00f5nis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genomics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "9" ] ] }, "page" : "397-406", "title" : "Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters.", "type" : "article-journal", "volume" : "90" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[8]", "plainTextFormattedCitation" : "[8]", "previouslyFormattedCitation" : "[8]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[8]. The untranslated 3’ exons, through alternative splicing, lead to different transcripts that still contain common coding region at the 3′ end. Therefore, through the use of alternative promoters and splicing mechanisms, various different BDNF transcripts with alternative 5’ untranslated regions (UTRs) can be generated that all code for the same BDNF protein. Finally, two alternative polyadenylated transcription stop sites in exon IX can lead to transcripts with either short or long 3′ UTRs. A study has shown that while the short 3′ UTR BDNF mRNA variant is restricted to the cell body in hippocampal neurons, the long 3′ UTR mRNAs are also observed in dendrites ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2008.05.045", "ISSN" : "1097-4172", "PMID" : "18614020", "abstract" : "The brain produces two brain-derived neurotrophic factor (BDNF) transcripts, with either short or long 3' untranslated regions (3' UTRs). The physiological significance of the two forms of mRNAs encoding the same protein is unknown. Here, we show that the short and long 3' UTR BDNF mRNAs are involved in different cellular functions. The short 3' UTR mRNAs are restricted to somata, whereas the long 3' UTR mRNAs are also localized in dendrites. In a mouse mutant where the long 3' UTR is truncated, dendritic targeting of BDNF mRNAs is impaired. There is little BDNF in hippocampal dendrites despite normal levels of total BDNF protein. This mutant exhibits deficits in pruning and enlargement of dendritic spines, as well as selective impairment in long-term potentiation in dendrites, but not somata, of hippocampal neurons. These results provide insights into local and dendritic actions of BDNF and reveal a mechanism for differential regulation of subcellular functions of proteins.", "author" : [ { "dropping-particle" : "", "family" : "An", "given" : "Juan Ji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gharami", "given" : "Kusumika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liao", "given" : "Guey-Ying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Woo", "given" : "Newton H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lau", "given" : "Anthony G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vanevski", "given" : "Filip", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Torre", "given" : "Enrique R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "Kevin R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feng", "given" : "Yue", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "Bai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Baoji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2008", "7", "11" ] ] }, "page" : "175-87", "title" : "Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons.", "type" : "article-journal", "volume" : "134" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[9]", "plainTextFormattedCitation" : "[9]", "previouslyFormattedCitation" : "[9]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[9]. Together, in the human brain, all exons are expressed, but to different degrees in different brain structures (for review see ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/tp.2016.214", "ISSN" : "2158-3188", "abstract" : "The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders", "author" : [ { "dropping-particle" : "", "family" : "Cattaneo", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cattane", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Begni", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pariante", "given" : "C M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riva", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Translational Psychiatry", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2016", "11", "22" ] ] }, "page" : "e958-e958", "publisher" : "Nature Publishing Group", "title" : "The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[10]", "plainTextFormattedCitation" : "[10]", "previouslyFormattedCitation" : "[10]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[10]). It is thought that these different promoters allow?BDNF?to respond to a greater variety of stimuli that further result in the generation of different transcripts that are stable in multiple intracellular environments ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ygeno.2007.05.004", "ISSN" : "0888-7543", "PMID" : "17629449", "abstract" : "Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has central roles in the development, physiology, and pathology of the nervous system. We have elucidated the structure of the human BDNF gene, identified alternative transcripts, and studied their expression in adult human tissues and brain regions. In addition, the transcription initiation sites for human BDNF transcripts were determined and the activities of BDNF promoters were analyzed in transient overexpression assays. Our results show that the human BDNF gene has 11 exons and nine functional promoters that are used tissue and brain-region specifically. Furthermore, noncoding natural antisense RNAs that display complex splicing and expression patterns are transcribed in the BDNF gene locus from the antiBDNF gene (approved gene symbol BDNFOS). We show that BDNF and antiBDNF transcripts form dsRNA duplexes in the brain in vivo, suggesting an important role for antiBDNF in regulating BDNF expression in human.", "author" : [ { "dropping-particle" : "", "family" : "Pruunsild", "given" : "Priit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kazantseva", "given" : "Anna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aid", "given" : "Tamara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Palm", "given" : "Kaia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Timmusk", "given" : "T\u00f5nis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genomics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "9" ] ] }, "page" : "397-406", "title" : "Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters.", "type" : "article-journal", "volume" : "90" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[8]", "plainTextFormattedCitation" : "[8]", "previouslyFormattedCitation" : "[8]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[8]. As?BDNF?promoters mediate differential?BDNF?isoform expression in various parts of the brain, it is thought that changes to their activity could affect cellular and behavioural phenotypes ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/ajmg.b.32616", "ISSN" : "15524841", "author" : [ { "dropping-particle" : "", "family" : "Hing", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sathyaputri", "given" : "Leela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Potash", "given" : "James B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Medical Genetics Part B: Neuropsychiatric Genetics", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2018", "3", "1" ] ] }, "page" : "143-167", "publisher" : "John Wiley & Sons, Ltd", "title" : "A comprehensive review of genetic and epigenetic mechanisms that regulate <i>BDNF</i> expression and function with relevance to major depressive disorder", "type" : "article-journal", "volume" : "177" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[11]", "plainTextFormattedCitation" : "[11]", "previouslyFormattedCitation" : "[11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[11]. Epigenetic mechanisms, predominantly promoter methylation that generally serves to silence gene expression, have been shown to regulate BDNF expression ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/jhg.2013.65", "ISSN" : "1434-5161", "PMID" : "23739121", "abstract" : "Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor, which is important for neuronal survival, development and synaptic plasticity. Accumulating evidence suggests that epigenetic modifications of BDNF are associated with the pathophysiology of psychiatric disorders, such as schizophrenia and mood disorders. Patients with psychiatric disorders generally show decreased neural BDNF levels, which are often associated with increased DNA methylation at the specific BDNF promoters. Importantly, observed DNA methylation changes are consistent across tissues including brain and peripheral blood, which suggests potential usefulness of these findings as a biomarker of psychiatric disorders. Here we review DNA methylation characteristics of BDNF promoters of cellular, animal and clinical samples and discuss future perspectives.", "author" : [ { "dropping-particle" : "", "family" : "Ikegame", "given" : "Tempei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bundo", "given" : "Miki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murata", "given" : "Yui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kasai", "given" : "Kiyoto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kato", "given" : "Tadafumi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Iwamoto", "given" : "Kazuya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Human Genetics", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "7", "6" ] ] }, "page" : "434-438", "title" : "DNA methylation of the BDNF gene and its relevance to psychiatric disorders", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[12]", "plainTextFormattedCitation" : "[12]", "previouslyFormattedCitation" : "[12]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[12]. BDNF promoter IV is one of the most widely investigated promoters in the contest of DNA methylation changes associated with alterations in BDNF expression: For example McKinney et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/npp.2015.107", "ISSN" : "0893-133X", "PMID" : "25881116", "abstract" : "Expression of brain-derived neurotrophic factor (BDNF) and somatostatin (SST) mRNAs in the brain decreases progressively and robustly with age, and lower BDNF and SST expression in the brain has been observed in many brain disorders. BDNF is known to regulate SST expression; however, the mechanisms underlying decreased expression of both genes are not understood. DNA methylation (DNAm) is an attractive candidate mechanism. To investigate the contribution of DNAm to the age-related decline in BDNF and SST expression, the Illumina Infinium HumanMethylation450 Beadchip Array was used to quantify DNAm of BDNF (26 CpG loci) and SST (9 CpG loci) in the orbital frontal cortices of postmortem brains from 22 younger (age <42 years) and 22 older individuals (age >60 years) with known age-dependent BDNF and SST expression differences. Relative to the younger individuals, 10 of the 26 CpG loci in BDNF and 8 of the 9 CpG loci in SST were significantly hypermethylated in the older individuals. DNAm in BDNF exons/promoters I, II, and IV negatively correlated with BDNF expression (r=-0.37, p<0.05; r=-0.40, p<0.05; r=-0.24, p=0.07), and DNAm in SST 5' UTR and first exon/intron negatively correlated with SST expression (r=-0.48, p<0.01; r=-0.63, p<0.001), respectively. An expanded set of BDNF- and GABA-related genes exhibited similar age-related changes in DNAm and correlation with gene expression. These results suggest that DNAm may be a proximal mechanism for decreased expression of BDNF, SST, and other BDNF- and GABA-related genes with brain aging and, by extension, for brain disorders in which their expression is decreased.", "author" : [ { "dropping-particle" : "", "family" : "McKinney", "given" : "Brandon C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lin", "given" : "Chien-Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oh", "given" : "Hyunjung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tseng", "given" : "George C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lewis", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibille", "given" : "Etienne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychopharmacology", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2015", "10", "16" ] ] }, "page" : "2604-2613", "title" : "Hypermethylation of BDNF and SST Genes in the Orbital Frontal Cortex of Older Individuals: A Putative Mechanism for Declining Gene Expression with Age", "type" : "article-journal", "volume" : "40" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[3]", "plainTextFormattedCitation" : "[3]", "previouslyFormattedCitation" : "[3]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[3] found in the orbital frontal cortex that DNA methyation at promoters I, II, and IV were increased in older people and negatively correlated with BDNF expression. Keller et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1001/archgenpsychiatry.2010.9", "ISSN" : "1538-3636", "PMID" : "20194826", "abstract" : "CONTEXT Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood. OBJECTIVES To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects. DESIGN Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. SETTING Academic medical center. PATIENTS OR OTHER PARTICIPANTS Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity. MAIN OUTCOME MEASURES The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area. RESULTS Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P < .001). Most of the CpG sites lying in the -300/+500 region, on both strands, had low or no methylation, with the exception of a few sites located near the transcriptional start site that had differential methylation, while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels. CONCLUSIONS BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.", "author" : [ { "dropping-particle" : "", "family" : "Keller", "given" : "Simona", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sarchiapone", "given" : "Marco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zarrilli", "given" : "Federica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Videtic", "given" : "Alja", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferraro", "given" : "Angelo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carli", "given" : "Vladimir", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sacchetti", "given" : "Silvana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lembo", "given" : "Francesca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Angiolillo", "given" : "Antonella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jovanovic", "given" : "Nikolina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pisanti", "given" : "Francesco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tomaiuolo", "given" : "Rossella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monticelli", "given" : "Antonella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Balazic", "given" : "Joze", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roy", "given" : "Alec", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marusic", "given" : "Andrej", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cocozza", "given" : "Sergio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fusco", "given" : "Alfredo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruni", "given" : "Carmelo B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castaldo", "given" : "Giuseppe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chiariotti", "given" : "Lorenzo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of general psychiatry", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2010", "3", "1" ] ] }, "page" : "258-67", "title" : "Increased BDNF promoter methylation in the Wernicke area of suicide subjects.", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[13]", "plainTextFormattedCitation" : "[13]", "previouslyFormattedCitation" : "[13]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[13], for example found significant increases in DNA methylation at BDNF promoter IV in the Wernicke area from suicide subjects, when compared to controls, that correlated with lower mRNA levels for BDNF exon IV containing transcript. In the periphery, increased methylation at BDNF promoters I and IV have been found in blood DNA from patients with Mild Cognitive Impairment (MCI) compared to controls and increased methylation at CpGs in promoter IV predicted conversion from MCI to AD ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3233/JAD-160954", "ISSN" : "13872877", "PMID" : "27935556", "abstract" : "Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer's disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n\u200a=\u200a458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n\u200a=\u200a330) and AD-conversion group (n\u200a=\u200a128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817-0.983, p\u200a<\u200a0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR\u200a=\u200a1.96, 95% CI: 1.07-2.98, p\u200a<\u200a0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR\u200a=\u200a3.51, p\u200a=\u200a0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD.", "author" : [ { "dropping-particle" : "", "family" : "Xie", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Yao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Zanchao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Wenxuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Rui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cui", "given" : "Dongsheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Qingfu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Shunjiang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Alzheimer's Disease", "editor" : [ { "dropping-particle" : "", "family" : "Zhu", "given" : "Ling-Qiang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2017", "1", "12" ] ] }, "page" : "391-401", "title" : "Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer\u2019s Disease: A 5-Year Longitudinal Study", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[14]", "plainTextFormattedCitation" : "[14]", "previouslyFormattedCitation" : "[14]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[14]. Further studies in blood DNA have shown increased BDNF methylation at promoter I in AD cases compared to controls ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0110773", "ISSN" : "1932-6203", "PMID" : "25364831", "abstract" : "Brain derived neurotrophic factor (BDNF) has been known to play an important role in various mental disorders or diseases such as Alzheimer's disease (AD). The aim of our study was to assess whether BDNF promoter methylation in peripheral blood was able to predict the risk of AD. A total of 44 AD patients and 62 age- and gender-matched controls were recruited in the current case-control study. Using the bisulphite pyrosequencing technology, we evaluated four CpG sites in the promoter of the BDNF. Our results showed that BDNF methylation was significantly higher in AD cases than in the controls (CpG1: p\u200a=\u200a10.021; CpG2: p\u200a=\u200a0.002; CpG3: p\u200a=\u200a0.007; CpG4: p\u200a=\u200a0.005; average methylation: p\u200a=\u200a0.004). In addition, BDNF promoter methylation was shown to be significantly correlated with the levels of alkaline phosphatase (ALP), glucose, Lp(a), ApoE and ApoA in males (ALP: r\u200a=\u200a-0.308, p\u200a=\u200a0.042; glucose: r\u200a=\u200a-0.383, p\u200a=\u200a0.010; Lp(a): r\u200a=\u200a0.333, p\u200a=\u200a0.027; ApoE: r\u200a=\u200a-0.345, p\u200a=\u200a0.032;), ApoA levels in females (r\u200a=\u200a0.362, p\u200a=\u200a0.033), and C Reactive Protein (CRP) levels in both genders (males: r\u200a=\u200a-0.373, p\u200a=\u200a0.016; females: r\u200a=\u200a-0.399, p\u200a=\u200a0.021). Our work suggested that peripheral BDNF promoter methylation might be a diagnostic marker of AD risk, although its underlying function remains to be elaborated in the future.", "author" : [ { "dropping-particle" : "", "family" : "Chang", "given" : "Lan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Yunliang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ji", "given" : "Huihui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dai", "given" : "Dongjun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Xuting", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Danjie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hong", "given" : "Qingxiao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ye", "given" : "Huadan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Xiaonan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhou", "given" : "Xiaohui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Jinfeng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Zhongming", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Ying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhou", "given" : "Dongsheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhuo", "given" : "Renjie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Yuzheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yin", "given" : "Honglei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mao", "given" : "Congcong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duan", "given" : "Shiwei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Qinwen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Chiariotti", "given" : "Lorenzo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2014", "11", "3" ] ] }, "page" : "e110773", "title" : "Elevation of Peripheral BDNF Promoter Methylation Links to the Risk of Alzheimer's Disease", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1159/000375367", "ISSN" : "1664-5464", "PMID" : "25873928", "abstract" : "BACKGROUND/AIMS In the present study, we examined whether DNA methylation of the brain-derived neurotrophic factor (BDNF) promoter is associated with the manifestation and clinical presentation of Alzheimer's disease (AD). METHODS Of 20 patients with AD and 20 age-matched normal controls (NCs), the DNA methylation of the BDNF promoter (measured using peripheral blood samples) was completely analyzed in 12 patients with AD and 6 NCs. The resulting methylation levels were compared statistically. Next, we investigated the correlation between the DNA methylation levels and the clinical presentation of AD. RESULTS The total methylation ratio (in %) of the 20 CpG sites was significantly higher in the AD patients (5.08 \u00b1 5.52%) than in the NCs (2.09 \u00b1 0.81%; p < 0.05). Of the 20 CpG sites, the methylation level at the CpG4 site was significantly higher in the AD subjects than in the NCs (p < 0.05). Moreover, the methylation level was significantly and negatively correlated with some neuropsychological test subscores (registration, recall, and prehension behavior scores; p < 0.05). CONCLUSION These results suggest that the DNA methylation of the BDNF promoter may significantly influence the manifestation of AD and might be associated with its neurocognitive presentation.", "author" : [ { "dropping-particle" : "", "family" : "Nagata", "given" : "Tomoyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kobayashi", "given" : "Nobuyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ishii", "given" : "Jumpei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shinagawa", "given" : "Shunichiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nakayama", "given" : "Ritsuko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shibata", "given" : "Nobuto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuerban", "given" : "Bolati", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohnuma", "given" : "Tohru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kondo", "given" : "Kazuhiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Arai", "given" : "Heii", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yamada", "given" : "Hisashi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nakayama", "given" : "Kazuhiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Dementia and geriatric cognitive disorders extra", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "64-73", "publisher" : "Karger Publishers", "title" : "Association between DNA Methylation of the BDNF Promoter Region and Clinical Presentation in Alzheimer's Disease.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[15,16]", "plainTextFormattedCitation" : "[15,16]", "previouslyFormattedCitation" : "[15,16]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[15,16] and increased peripheral BDNF promoter I and IV in amnestic MCI compared to controls that further predicted the conversion from MCI to AD ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3233/JAD-160954", "ISSN" : "13872877", "PMID" : "27935556", "abstract" : "Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer's disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n\u200a=\u200a458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n\u200a=\u200a330) and AD-conversion group (n\u200a=\u200a128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817-0.983, p\u200a<\u200a0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR\u200a=\u200a1.96, 95% CI: 1.07-2.98, p\u200a<\u200a0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR\u200a=\u200a3.51, p\u200a=\u200a0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD.", "author" : [ { "dropping-particle" : "", "family" : "Xie", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Yao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Zanchao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Wenxuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Rui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cui", "given" : "Dongsheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Qingfu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Shunjiang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Alzheimer's Disease", "editor" : [ { "dropping-particle" : "", "family" : "Zhu", "given" : "Ling-Qiang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2017", "1", "12" ] ] }, "page" : "391-401", "title" : "Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer\u2019s Disease: A 5-Year Longitudinal Study", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[14]", "plainTextFormattedCitation" : "[14]", "previouslyFormattedCitation" : "[14]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[14]. Interestingly, the conversion from amnestic MCI to AD depended upon an interaction of methylation with a non-synonymous single nucleotide polymorphism (SNP) in the BDNF gene, rs6265 ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3233/JAD-170007", "ISSN" : "13872877", "PMID" : "28387675", "abstract" : "Alzheimer's disease (AD) is a complex multifactorial disease influenced by both genetic and epigenetic factors. This study was aimed to evaluate the interaction between brain-derived neurotrophic factor (BDNF) promoter methylation status and tag single nucleotide polymorphisms (tag SNPs) on amnestic mild cognitive impairment (aMCI) and its conversion to AD. A total of 506 aMCI patients and 728 cognitive normal controls were included in the cross-sectional analysis. Patients (n\u200a=\u200a458) from aMCI cohort were selected in the 5-year longitudinal study and classified into two groups: aMCI-stable group (n\u200a=\u200a330) and AD-conversion group (n\u200a=\u200a128). BDNF promoter methylation was detected by bisulfite-PCR amplification and pyrosequencing. Seven tag SNPs were genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Elevation of BDNF promoter methylation status was associated with aMCI and AD conversion. The higher methylation levels at CpG5 site showed significant main interactive effects between group and time (F\u200a=\u200a8.827, p\u200a=\u200a0.005). Genetic analysis revealed rs2030324 and rs6265 were associated with aMCI and rs6265 was associated with AD conversion. The interaction between DNA methylation of CpG5 and AA genotype of rs6265 had a risk role in the development of aMCI (p\u200a=\u200a0.019, OR\u200a=\u200a1.233, 95% CI: 1.117-1.303) and its progression to AD (p\u200a=\u200a0.003, OR\u200a=\u200a1.399, 95% CI: 1.198-1.477). The interactions between DNA methylation (CpG5) of the BDNF gene promoter and the tag SNP (rs6265) play important roles in the etiology of aMCI and its conversion to AD.", "author" : [ { "dropping-particle" : "", "family" : "Xie", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Zanchao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Wenxuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Rui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cui", "given" : "Dongsheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Qingfu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Shunjiang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Alzheimer's Disease", "editor" : [ { "dropping-particle" : "", "family" : "Zhu", "given" : "Ling-Qiang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2017", "5", "3" ] ] }, "page" : "263-274", "title" : "DNA Methylation and Tag SNPs of the BDNF Gene in Conversion of Amnestic Mild Cognitive Impairment into Alzheimer\u2019s Disease: A Cross-Sectional Cohort Study", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[17]", "plainTextFormattedCitation" : "[17]", "previouslyFormattedCitation" : "[17]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[17]. However there are some conflicting reports not finding increased BDNF methylation in peripheral DNA in AD compared to controls ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0110773", "ISSN" : "1932-6203", "PMID" : "25364831", "abstract" : "Brain derived neurotrophic factor (BDNF) has been known to play an important role in various mental disorders or diseases such as Alzheimer's disease (AD). The aim of our study was to assess whether BDNF promoter methylation in peripheral blood was able to predict the risk of AD. A total of 44 AD patients and 62 age- and gender-matched controls were recruited in the current case-control study. Using the bisulphite pyrosequencing technology, we evaluated four CpG sites in the promoter of the BDNF. Our results showed that BDNF methylation was significantly higher in AD cases than in the controls (CpG1: p\u200a=\u200a10.021; CpG2: p\u200a=\u200a0.002; CpG3: p\u200a=\u200a0.007; CpG4: p\u200a=\u200a0.005; average methylation: p\u200a=\u200a0.004). In addition, BDNF promoter methylation was shown to be significantly correlated with the levels of alkaline phosphatase (ALP), glucose, Lp(a), ApoE and ApoA in males (ALP: r\u200a=\u200a-0.308, p\u200a=\u200a0.042; glucose: r\u200a=\u200a-0.383, p\u200a=\u200a0.010; Lp(a): r\u200a=\u200a0.333, p\u200a=\u200a0.027; ApoE: r\u200a=\u200a-0.345, p\u200a=\u200a0.032;), ApoA levels in females (r\u200a=\u200a0.362, p\u200a=\u200a0.033), and C Reactive Protein (CRP) levels in both genders (males: r\u200a=\u200a-0.373, p\u200a=\u200a0.016; females: r\u200a=\u200a-0.399, p\u200a=\u200a0.021). Our work suggested that peripheral BDNF promoter methylation might be a diagnostic marker of AD risk, although its underlying function remains to be elaborated in the future.", "author" : [ { "dropping-particle" : "", "family" : "Chang", "given" : "Lan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Yunliang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ji", "given" : "Huihui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dai", "given" : "Dongjun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Xuting", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jiang", "given" : "Danjie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hong", "given" : "Qingxiao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ye", "given" : "Huadan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Xiaonan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhou", "given" : "Xiaohui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Jinfeng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Zhongming", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Ying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhou", "given" : "Dongsheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhuo", "given" : "Renjie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Yuzheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yin", "given" : "Honglei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mao", "given" : "Congcong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duan", "given" : "Shiwei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Qinwen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Chiariotti", "given" : "Lorenzo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2014", "11", "3" ] ] }, "page" : "e110773", "title" : "Elevation of Peripheral BDNF Promoter Methylation Links to the Risk of Alzheimer's Disease", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.neulet.2015.08.012", "ISSN" : "03043940", "PMID" : "26275347", "abstract" : "The identification of Alzheimer's disease (AD) biomarkers is crucial to support drug discovery. Within putative biomarkers, peripheral Bdnf levels correlate with cognitive decline and AD, although conflicting findings are reported. Sirtuin 1 (Sirt1) serum levels are lower in AD patients and Presenilin 1 (Psen1) is expressed by blood cells. DNA methylation is altered in AD patients, suggesting that epigenetic mechanisms play a role in AD pathophysiology. The objective of this study was to investigate promoter methylation levels of potential biomarkers in AD cases and controls. Peripheral blood DNA methylation levels were analysed by methylation-specific primer real-time PCR. Bdnf promoter methylation levels did not differ between AD patients and controls. Similarly, Sirt1 promoter revealed minimal levels of methylation which did not display significant differences between groups. No significant difference was revealed between AD patients and controls also in Psen1 methylation, showing a large variability of values among subjects. Although peripheral Bdnf expression is associated with differential promoter methylation in psychiatric and neurological disorders, our results suggest that different mechanisms take place in AD. The finding that the control of Sirt1 protein levels in blood is not exerted through the repression of mRNA expression by promoter hypermethylation is in agreement with previous data. In contrast, other studies reported that Psen1 methylation may be increased or decreased in AD patients, suggesting that additional studies are required. In conclusion, this study shows that peripheral levels of the potential AD biomarker proteins Bdnf, Sirt1, and Psen1 are not regulated by different promoter methylation.", "author" : [ { "dropping-particle" : "", "family" : "Carboni", "given" : "Lucia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lattanzio", "given" : "Francesca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Candeletti", "given" : "Sanzio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porcellini", "given" : "Elisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Raschi", "given" : "Elena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Licastro", "given" : "Federico", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Romualdi", "given" : "Patrizia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuroscience Letters", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2015", "9", "25" ] ] }, "page" : "44-48", "title" : "Peripheral leukocyte expression of the potential biomarker proteins Bdnf, Sirt1, and Psen1 is not regulated by promoter methylation in Alzheimer's disease patients", "type" : "article-journal", "volume" : "605" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[15,18]", "plainTextFormattedCitation" : "[15,18]", "previouslyFormattedCitation" : "[15,18]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[15,18]. Within the CNS, Rao and colleagues ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/tp.2012.55", "ISSN" : "2158-3188", "PMID" : "22760556", "abstract" : "Alzheimer's disease (AD) and bipolar disorder (BD) are progressive brain disorders. Upregulated mRNA and protein levels of neuroinflammatory and arachidonic acid (AA) markers with loss of synaptic markers (synaptophysin and drebrin) have been reported in brain tissue from AD and BD patients. We hypothesized that some of these changes are associated with epigenetic modifications of relevant genes. To test this, we measured gene-specific CpG methylation, global DNA methylation and histone modifications in postmortem frontal cortex from BD (n=10) and AD (n=10) patients and respective age-matched controls (10 per group). AD and BD brains showed several epigenetic similarities, including global DNA hypermethylation, and histone H3 phosphorylation. These changes were associated with hypo- and hypermethylation of CpG islands in cyclooxygenase-2 and brain-derived neurotrophic factor promoter regions, respectively. Only the AD brain showed hyper- and hypomethylated CpG islands in promoter regions for cAMP response element-binding protein and nuclear transcription factor kappa B genes, respectively. Only the BD brain demonstrated increased global histone H3 acetylation and hypermethylation of the promotor region for the drebrin-like protein gene. There was no significant epigenetic modification for 12-lipooxygenase or p450 epoxygenase in either illness. Many observed epigenetic changes were inversely related to respective changes in mRNA and protein levels. These epigenetic modifications involving neuroinflammatory, AA cascade and synaptic markers may contribute to progression in AD and BD and identify new targets for drug development.", "author" : [ { "dropping-particle" : "", "family" : "Rao", "given" : "J S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keleshian", "given" : "V L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rapoport", "given" : "S I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Translational psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2012", "7", "3" ] ] }, "page" : "e132", "publisher" : "Nature Publishing Group", "title" : "Epigenetic modifications in frontal cortex from Alzheimer's disease and bipolar disorder patients.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[19]", "plainTextFormattedCitation" : "[19]", "previouslyFormattedCitation" : "[19]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[19], studying groups of 10 AD and 10 control prefrontal cortex samples, found significant decrease in total BDNF mRNA in the AD brain compared to control brains together with increased promoter DNA methylation. A reduction in prefrontal cortex BDNF expression in AD has also been found in a study by Buchman et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/tp.2012.55", "ISSN" : "2158-3188", "PMID" : "22760556", "abstract" : "Alzheimer's disease (AD) and bipolar disorder (BD) are progressive brain disorders. Upregulated mRNA and protein levels of neuroinflammatory and arachidonic acid (AA) markers with loss of synaptic markers (synaptophysin and drebrin) have been reported in brain tissue from AD and BD patients. We hypothesized that some of these changes are associated with epigenetic modifications of relevant genes. To test this, we measured gene-specific CpG methylation, global DNA methylation and histone modifications in postmortem frontal cortex from BD (n=10) and AD (n=10) patients and respective age-matched controls (10 per group). AD and BD brains showed several epigenetic similarities, including global DNA hypermethylation, and histone H3 phosphorylation. These changes were associated with hypo- and hypermethylation of CpG islands in cyclooxygenase-2 and brain-derived neurotrophic factor promoter regions, respectively. Only the AD brain showed hyper- and hypomethylated CpG islands in promoter regions for cAMP response element-binding protein and nuclear transcription factor kappa B genes, respectively. Only the BD brain demonstrated increased global histone H3 acetylation and hypermethylation of the promotor region for the drebrin-like protein gene. There was no significant epigenetic modification for 12-lipooxygenase or p450 epoxygenase in either illness. Many observed epigenetic changes were inversely related to respective changes in mRNA and protein levels. These epigenetic modifications involving neuroinflammatory, AA cascade and synaptic markers may contribute to progression in AD and BD and identify new targets for drug development.", "author" : [ { "dropping-particle" : "", "family" : "Rao", "given" : "J S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keleshian", "given" : "V L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klein", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rapoport", "given" : "S I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Translational psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2012", "7", "3" ] ] }, "page" : "e132", "publisher" : "Nature Publishing Group", "title" : "Epigenetic modifications in frontal cortex from Alzheimer's disease and bipolar disorder patients.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[19]", "plainTextFormattedCitation" : "[19]", "previouslyFormattedCitation" : "[19]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[19] on 535 older participants. Li et al. [29] found a reduction in temporal cortex and frontal cortex in AD, but specifically in females. They further found that rs6265 associated with transcriptional regulation only in the female brains. Garzon et al. investigating individual BDNF variants found transcript specific decreases of BDNF in AD brains. Few studies have investigated together the epigenetic, genetic, transcriptional and translational regulation of this peptide in the brain in relation to AD.The aim of this study was to investigate mechanisms underlying the dysregulation of BDNF within the AD brains studying human prefrontal cortex tissue for BDNF protein levels, promoter-specific expression, promoter DNA methylation specifically at promoters for exons I and IV and the rs6265 genotype.MethodsStudy populationFresh, frozen tissue was taken from superior frontal gyrus (Brodmann area 8). Samples were acquired from donors through the Manchester Brain Bank. Ethical approval was granted from the Manchester Brain Bank Committee. Donors were participants of a large prospective cognitive ageing cohort known as The University of Manchester Age and Cognitive Performance Research Cohort ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1080/13825580490511116", "ISSN" : "1382-5585", "abstract" : "This paper describes the participants, design, method and tests used during a 20-year longitudinal study of cognitive changes in increasing age experienced by 6542 healthy residents of Greater Manchester and Newcastle-upon-Tyne, then aged from 42 to 92 years. Information collected and updated includes demographics and health, scores on two, biennially alternated batteries of cognitive tests, repeated administrations of the Beck and Yesavage depression inventories and of self-reports of stressful life events, self-evaluation and locus of control questionnaires and detailed information on lifestyle, hobbies and occupations, physical and social activities, family circumstances and health history. Records have allowed investigation of rates of cognitive changes from 36 months to 20 years preceding death from a variety of causes. Collection of blood and saliva provide, blood chemistry and cortisol levels to analyse associations of rates of cognitive change to genetic factors, blood chemistry and cortisol level...", "author" : [ { "dropping-particle" : "", "family" : "Rabbitt", "given" : "P.M.A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McInnes", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diggle", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holland", "given" : "F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bent", "given" : "N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abson", "given" : "V.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pendleton", "given" : "N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Horan", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Aging, Neuropsychology, and Cognition", "id" : "ITEM-1", "issue" : "2-3", "issued" : { "date-parts" : [ [ "2004", "6" ] ] }, "page" : "245-279", "publisher" : " Taylor & Francis Group ", "title" : "The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, 1983 through 2003", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.3233/JAD-180171", "ISSN" : "13872877", "PMID" : "29865073", "abstract" : "The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), \u03b1-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOE\u025b4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOE\u025b2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.", "author" : [ { "dropping-particle" : "", "family" : "Robinson", "given" : "Andrew C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davidson", "given" : "Yvonne S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Horan", "given" : "Michael A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pendleton", "given" : "Neil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mann", "given" : "David M.A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Alzheimer's Disease", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2018", "6", "19" ] ] }, "page" : "483-496", "title" : "Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age", "type" : "article-journal", "volume" : "64" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[20,21]", "plainTextFormattedCitation" : "[20,21]", "previouslyFormattedCitation" : "[20,21]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[20,21] and included all those with brain material and available neuropathological data. All participants are white British, (Supplementary Table 1)Stratification into Alzheimer’s disease neuropathology groups were based on the National Institute on Aging-Alzheimer’s Association guidelines ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jalz.2011.10.007", "ISSN" : "1552-5279", "PMID" : "22265587", "abstract" : "A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.", "author" : [ { "dropping-particle" : "", "family" : "Hyman", "given" : "Bradley T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phelps", "given" : "Creighton H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beach", "given" : "Thomas G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bigio", "given" : "Eileen H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cairns", "given" : "Nigel J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carrillo", "given" : "Maria C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickson", "given" : "Dennis W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duyckaerts", "given" : "Charles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frosch", "given" : "Matthew P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Masliah", "given" : "Eliezer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mirra", "given" : "Suzanne S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nelson", "given" : "Peter T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schneider", "given" : "Julie A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thal", "given" : "Dietmar Rudolf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thies", "given" : "Bill", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trojanowski", "given" : "John Q", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Vinters", "given" : "Harry", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montine", "given" : "Thomas J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Alzheimer's & dementia : the journal of the Alzheimer's Association", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "1-13", "publisher" : "NIH Public Access", "title" : "National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[22]", "plainTextFormattedCitation" : "[22]", "previouslyFormattedCitation" : "[22]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[22]. Briefly, the amyloid beta (Aβ) plaque score (Thal), neurofibrillary tangle stage (Braak) and neuritic plaque score (CERAD) were used to create an “ABC” score. Four groups were determined: Not, Low, Intermediate and High AD neuropathologic change. Those with high levels of Aβ and neuritic plaques with low neurofibrillary tangle score were excluded (“ABC“ score: A2-3, B0-1, C0-3), due to potential contributions by other co-morbidities. Gene expression analysisBrain tissue (~30 mg) was extracted for RNA using TRIsure? (Bioline, UK), quantified using the Nanodrop 2000c (Thermo Scientific, Wilmington, USA) and qualifies using the Agilent Bioanalyser. RIN values are given in Supplementary Table 1. The Tetro cDNA synthesis kit (Bioline, UK) was used to reverse transcribe total RNA (2 μg), according to the manufacturer’s protocol using random hexamers. Relative gene expression was analysed using qPCR with SensiFASTTM SYBR? Lo-ROX kit (Bioline), in accordance with the manufacturer’s protocol using primers for BDNF exon I containing transcript (F: CAGCATCTGTTGGGGAGACGA; R: GCCACCTTGTCCTCGGATGT), BDNF exon IV containing transcript (F: TGGGAGTTTTGGGGCCGAAG; R: TGGTCATCACTCTTCTCACCTGG), BDNF total long 3’, (F: GGACCCTTCAGAGGTGGCTC; R: GTCGGCTTGAGTGTGGTCCT), ACTB (F: CATCCTCACCCTGAAGTACC; R: ATAGCAACGTACATGGCTGG) and GAPDH (F: CCGCATCTTCTTTTGCGTCG; R: TGGAATTTGCCATGGGTGGA). qPCR was performed on a Stratagene Mx3000P qPCR system (Agilent) in duplicate. Relative gene expression, accounting for primer efficiencies and normalised to GAPDH and ACTB, were determined using the geometric averaging method described by Vandesompele and colleagues ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1474-760X", "PMID" : "12184808", "abstract" : "BACKGROUND Gene-expression analysis is increasingly important in biological research, with real-time reverse transcription PCR (RT-PCR) becoming the method of choice for high-throughput and accurate expression profiling of selected genes. Given the increased sensitivity, reproducibility and large dynamic range of this methodology, the requirements for a proper internal control gene for normalization have become increasingly stringent. Although housekeeping gene expression has been reported to vary considerably, no systematic survey has properly determined the errors related to the common practice of using only one control gene, nor presented an adequate way of working around this problem. RESULTS We outline a robust and innovative strategy to identify the most stably expressed control genes in a given set of tissues, and to determine the minimum number of genes required to calculate a reliable normalization factor. We have evaluated ten housekeeping genes from different abundance and functional classes in various human tissues, and demonstrated that the conventional use of a single gene for normalization leads to relatively large errors in a significant proportion of samples tested. The geometric mean of multiple carefully selected housekeeping genes was validated as an accurate normalization factor by analyzing publicly available microarray data. CONCLUSIONS The normalization strategy presented here is a prerequisite for accurate RT-PCR expression profiling, which, among other things, opens up the possibility of studying the biological relevance of small expression differences.", "author" : [ { "dropping-particle" : "", "family" : "Vandesompele", "given" : "Jo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Preter", "given" : "Katleen", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pattyn", "given" : "Filip", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Poppe", "given" : "Bruce", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roy", "given" : "Nadine", "non-dropping-particle" : "Van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paepe", "given" : "Anne", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Speleman", "given" : "Frank", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genome biology", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2002", "6", "18" ] ] }, "page" : "RESEARCH0034", "title" : "Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.", "type" : "article-journal", "volume" : "3" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[23]", "plainTextFormattedCitation" : "[23]", "previouslyFormattedCitation" : "[23]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[23]. Those samples with gene expression levels were not detected (Ct ≥40) were excluded from analyses.GenotypingDNA samples were extracted from peripheral blood samples, as described previously ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.neurobiolaging.2017.11.009", "ISSN" : "1558-1497", "PMID" : "29223680", "abstract" : "Chronic low-grade inflammation during aging (inflammaging) is associated with cognitive decline and neurodegeneration; however, the mechanisms underlying inflammaging are unclear. We studied a population (n\u00a0= 361) of healthy young and old adults from the MyoAge cohort. Peripheral levels of C-X-C motif chemokine ligand 10 (CXCL10) was found to be higher in older adults, compared with young, and negatively associated with working memory performance. This coincided with an age-related reduction in blood DNA methylation at specific CpGs within the CXCL10 gene promoter. In\u00a0vitro analysis supported the role of DNA methylation in regulating CXCL10 transcription. A polymorphism (rs56061981) that altered methylation at one of these CpG sites further associated with working memory performance in 2 independent aging cohorts. Studying prefrontal cortex samples, we found higher CXCL10 protein levels in those with Alzheimer's disease, compared with aged controls. These findings support the association of peripheral inflammation, as demonstrated by CXCL10, in aging and cognitive decline. We reveal age-related epigenetic and genetic factors which contribute to the dysregulation of CXCL10.", "author" : [ { "dropping-particle" : "", "family" : "Bradburn", "given" : "Steven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McPhee", "given" : "Jamie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bagley", "given" : "Liam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carroll", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Slevin", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Al-Shanti", "given" : "Nasser", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barnouin", "given" : "Yoann", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hogrel", "given" : "Jean-Yves", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "P\u00e4\u00e4suke", "given" : "Mati", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gapeyeva", "given" : "Helena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maier", "given" : "Andrea", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sipil\u00e4", "given" : "Sarianna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Narici", "given" : "Marco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robinson", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mann", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Payton", "given" : "Antony", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pendleton", "given" : "Neil", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Butler-Browne", "given" : "Gillian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murgatroyd", "given" : "Chris", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurobiology of aging", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2018" ] ] }, "page" : "54-64", "publisher" : "Elsevier", "title" : "Dysregulation of C-X-C motif ligand 10 during aging and association with cognitive performance.", "type" : "article-journal", "volume" : "63" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[24]", "plainTextFormattedCitation" : "[24]", "previouslyFormattedCitation" : "[24]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[24]. Genotyping was performed using the Kompetitive Allele Specific PCR (KASP) assay (LGC Ltd) in reaction volumes of 10ul together with 5ng of DNA that was run on a Stratagene MX3000P qPCR machine (Agilent). Fluorescence values were read by the MXPro software to enable genotype calling.Protein quantificationBrain tissue (~100 mg) were lysed using RIPA buffer (Sigma) supplemented with 1x protease inhibitor cocktail and 0.1 M PMSF, as described previously ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/ageing/afw137", "ISSN" : "0002-0729", "PMID" : "27515675", "abstract" : "INTRODUCTION cognitive deterioration and reductions of bone health coincide with increasing age. We examine the relationship between bone composition and plasma markers of bone remodelling with measures of cognitive performance in healthy adults. METHODS this cross-sectional study included 225 old (52% women, mean age: 74.4\u00a0\u00b1\u00a03.3 years) and 134 young (52% women, mean age: 23.4\u00a0\u00b1\u00a02.7 years) adult participants from the MyoAge project. Whole body bone mineral density was measured by dual-energy X-ray absorptiometry. Blood analyses included a panel of bone-related peptides (dickkopf-1, osteoprotegerin, osteocalcin (OC), osteopontin, sclerostin, parathyroid hormone and fibroblast growth factor 23), as well as serum calcium and 25-hydroxy vitamin D assays. A selection of cognitive domains (working memory capacity, episodic memory, executive functioning and global cognition) was assessed with a standardised neuropsychological test battery. RESULTS adjusting for covariates and multiple testing revealed that plasma OC levels were positively associated with measures of executive functioning (\u03b2\u00a0=\u00a00.444, P <\u00a00.001) and global cognition (\u03b2\u00a0=\u00a00.381, P =\u00a00.001) in the older women. DISCUSSION these correlative results demonstrate a positive association between OC, a factor known to regulate bone remodelling, with cognitive performance in older non-demented women. Further work should address possible mechanistic interpretations in humans.", "author" : [ { "dropping-particle" : "", "family" : "Bradburn", "given" : "Steven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McPhee", "given" : "Jamie S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bagley", "given" : "Liam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sipila", "given" : "Sarianna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stenroth", "given" : "Lauri", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Narici", "given" : "Marco Vincenzo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "P\u00e4\u00e4suke", "given" : "Mati", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gapeyeva", "given" : "Helena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Osborne", "given" : "Gabrielle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sassano", "given" : "Lorraine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meskers", "given" : "Carel G. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maier", "given" : "Andrea B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hogrel", "given" : "Jean-Yves", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barnouin", "given" : "Yoann", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Butler-Browne", "given" : "Gillian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murgatroyd", "given" : "Chris", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Age and Ageing", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2016", "11" ] ] }, "page" : "844-849", "title" : "Association between osteocalcin and cognitive performance in healthy older adults", "type" : "article-journal", "volume" : "45" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[25]", "plainTextFormattedCitation" : "[25]", "previouslyFormattedCitation" : "[25]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[25]. Quantification of BDNF protein was performed using the Human/Mouse BDNF DuoSet ELISA (R&D Systems). Protein levels were normalised to total protein levels in the assay (pg/mg of total protein).DNA methylation analysisGenomic DNA was extracted using the Isolate II Genomic DNA kit (Bioline) and 500 ng bisulfite-converted using the EpiMark Bisulfite Conversion Kit (New England Biolabs). Primers were used to amplify regions of the BDNF promoter I (F: TGAGTGATGATTAAATGGGGATTG; R: BIO-ACTATTAACTCACATTTAAAAAACCATAAC; S: TGGGGATTGGGGGGA) and promoter IV (F: GATTTTGGTAATTCGTGTATTAGAGTGTT; R: BIO-AGATTAAATGGAGTTTTCGTTGAT; S: AATGGAGTTTTCGTTGATGGGGTGCA) using MyTaq HS mix PCR reagents (Bioline). The BDNF promoter I and promoter IV amplicons contained 5 and 9 CpG sites, respectively. Amplicons were processed on the Qiagen Q24 Workstation and sequenced on the Qiagen Q24 pyrosequencer. DNA methylation levels across each amplicon were averaged. See Supplemental Figure S1 for locations of the regions analysed.Statistical analysisAll analyses were performed using IBM SPSS Statistics (v.25). BDNF isoform expression, protein and DNA methylation levels were log10 transformed prior to statistical analysis. Correlations between gene expression, DNA methylation and protein levels with donor age were performed using Pearson correlation tests. Correlations between gene expression, DNA methylation and protein levels were performed using Partial correlation tests, with donor age as a covariate. Differences in gene expression, DNA methylation and protein levels between rs6265 variant groups were assessed using independent student t-tests. Further, differences between groups while controlling for donor age were assessed using a one-way ANCOVA. Differences in gene expression, DNA methylation and protein levels between AD neuropathological groups were assessed using one-way ANOVA, as well as a one-way ANCOVA to control for age. Results are presented as mean and standard deviation, unless otherwise stated. Statistical significance was accepted when P<0.05.ResultsClinical and pathological characteristics of the study population can be found in Table 1.Table 1. Clinicopathological characteristics for the donor samples. CharacteristicMean (SD)Age at death (years)87.5 (6.1)Sex (male/female)21/46Post-mortem delay (hours)a76.1 (43.7)Brain weight (g)b1207.4 (137.4)BDNF rs6265 (N)Val/Val39 (58%)Val/Met25 (37%)Met/Met3 (5%)Thal score (N)0 (A0)17 (25%)1 (A1)11 (16%)2 (A2)6 (9%)3 (A2)17 (25%)4 (A3)9 (13%)5 (A3)7 (10%)Braak score (N)c0 (B0)4 (6%)I (B1)11 (16%)II (B1)18 (27%)III (B2)13 (19%)IV (B2)12 (18%)V (B3)6 (9%)VI (B3)2 (3%)CERAD score (N)None (C0)18 (27%)Sparse (C1)19 (28%)Moderate (C2)18 (27%)Frequent (C3)12 (18%)a N = 60b N = 43c N = 66Relationship between BDNF gene expression, DNA methylation and protein levels with ageThe association between BDNF exon I, IV and total long 3’ isoform expression with the age at death of donors was investigated (Figure 1). There was a negative association between expression of exon IV containing (r = -0.291, P = 0.020; Figure 1B) and total long 3’ (r = -0.354, P = 0.004; Figure 1C) BDNF isoforms with age, however, no relationships were evident for BDNF exon I containing isoform (r = -0.201, P = 0.149; Figure 1A).There were no associations between BDNF protein levels (r = -0.143, P = 0.256) or DNA methylation levels (promoter I: r = -0.038, P = 0.761; promoter IV: r = 0.177, P = 0.156) with donor ages.BDNF protein levels (pg/ml) did not differ between females (117.5± 48.549) and males (127.022±36.528) = -0.783, p=0.437. There were also no differences in expression of BDNF exon-4 containing transcripts (p=0.597) and total long 3’UTR (p=0.39) between genders, however there was significantly increased BDNF exon-1 containing transcripts in males than females (p=0.001). Regarding DNA methylation, there were no significant differences between genders in BDNF promoter 1 (p=0.425) and promoter 4 (p=0.606) methylation. Correlations between BDNF gene expression, DNA methylation and protein levelsThe relationships between BDNF gene expression, DNA methylation and protein levels can be seen in Table 2. Since donor age significantly correlated with BDNF gene expression, correlations were controlled for donor ages throughout. Briefly, BDNF exon I isoform expression positively correlated with BDNF exon IV and total long 3’ isoform expression. BDNF exon IV expression did not correlate with total long 3’ variant expression. Promoter I DNA methylation negatively correlated with BDNF exon I isoform expression levels, however this correlation was lost (p=0.08) when account for RIN values (Supplementary Table S2). However, there were no associations between promoter IV methylation and BDNF exon IV isoform expression levels. Protein levels were not associated with either BNDF exon I, exon IV or total long 3’UTR RNA expression or DNA methylation levels.Table 2. Partial correlation matrix, controlling for donor ages, between BDNF gene expression, DNA methylation and protein levelsGene expressionDNA methylationBDNF IBDNF IVBDNF TotalPromoter IPromoter IVProteinBDNF IBDNF IV0.586***BDNF Total0.327*-0.233?Promoter I-0.282*-0.181-0.206Promoter IV-0.0910.015-0.0070.383Protein0.251?0.0180.0540.0740.044Results displayed are partial correlation coefficient values. ? P < 0.10. * P < 0.05. *** P < 0.001.Relationship between BDNF gene expression, DNA methylation and protein levels with rs6265 variant The rs6265 variant was in Hardy-Weinberg equilibrium in the study population (X2 = 0.162, P = 0.687). To explore the differences in BDNF gene expression levels with the rs6265 variant, donors were stratified into Val-homozygotes and Met-allele carriers. There were no differences in BDNF exon I (t = -1.592, P = 0.118) and total long 3’ (t = 0.122, P = 0.904) variant gene expression levels between the two groups. However, the Met-allele carriers had significantly higher BDNF exon IV isoform expression compared to Val-homozygotes (t = -2.640, P = 0.010) (Figure 2). This difference remained after controlling for donor age at death (F = 6.455, P = 0.014) and age AND RIN values (F = 7.229, P = 0.009).There were no differences in BDNF protein levels (t = 0.446, P = 0.657) or DNA methylation levels (promoter 1: -0.435, P = 0.665; promoter 4: -0.755, P = 0.453) between rs6265 variants. Relationship between BDNF gene expression, DNA methylation and protein levels with Alzheimer’s disease pathologyTo investigate the difference in BDNF gene expression with AD pathology, donors were stratified based on the NIA-AA “ABC” score, which considers the amyloid plaque, neuritic plaque and neurofibrillary tangle scores. These groups were Not, Low, Intermediate and High AD neuropathological change.Overall, there were differences in BDNF total long 3’ isoform gene expression levels between AD pathological groups (F = 3.074, P = 0.035). Specifically, inter-group comparisons revealed a significant downregulation of BDNF total long 3’, isoform expression in the Low AD group, compared to the Not AD group (P = 0.021) (Figure 3). This difference was also apparent when accounting for donor age at death (overall comparison: F = 3.323, P = 0.026; post-hoc comparison: P = 0.021), however when including age AND RIN values, there were no differences (F = 1.909, P = 0.139).There were no differences in BDNF exon I (F = 2.766, P = 0.053) or IV (F = 0.405, P = 0.750) isoform expression levels between the AD neuropathological groups. Further, there were no differences in protein (F = 0.953, P = 0.421) or DNA methylation (promoter 1: F = 1.019, P = 0.391; promoter 4: F = 1.009, P = 0.396) levels between groups.DiscussionIn the prefrontal cortex, BDNF gene expression was associated with donor age, rs6265 carrier status and early AD neuropathology in a variant-specific manner. These associations were independent of any influences of DNA methylation or protein levels. Thus, we provide further evidence to the complex mechanisms dysregulating central BDNF during ageing and neurodegeneration.The majority of research investigating age associations of BDNF levels in humans has focussed on peripheral measures. Specifically, many reports suggest a gradual reduction in plasma and serum concentrations during ageing ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/gerona/glu028", "ISSN" : "1079-5006", "author" : [ { "dropping-particle" : "", "family" : "Passaro", "given" : "Angela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dalla Nora", "given" : "Edoardo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morieri", "given" : "Mario L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soavi", "given" : "Cecilia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanz", "given" : "Juana M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zurlo", "given" : "Amedeo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fellin", "given" : "Renato", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zuliani", "given" : "Giovanni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journals of Gerontology Series A: Biological Sciences and Medical Sciences", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2015", "3", "1" ] ] }, "page" : "294-302", "publisher" : "Oxford University Press", "title" : "Brain-Derived Neurotrophic Factor Plasma Levels: Relationship With Dementia and Diabetes in the Elderly Population", "type" : "article-journal", "volume" : "70" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/J.NEUROBIOLAGING.2004.03.002", "ISSN" : "0197-4580", "abstract" : "Brain-derived neurotrophic factor (BDNF) is a key mediator of neuronal plasticity in the adult. BDNF is known to be stored in human platelets and to circulate in plasma, but the regulation and function of BDNF in peripheral blood is still poorly understood. In this prospective study, we have examined 140 healthy, non-allergic adults (20\u201360 years old) to elucidate the impact of age and physical parameters on BDNF levels in human platelets and plasma. There was a wide concentration range of BDNF in serum (median: 22.6ng/ml), platelets (median: 92.7pg/106 platelets) and plasma (median: 92.5pg/ml). BDNF levels in plasma decreased significantly with increasing age or weight, whereas platelet levels did not. When matched for weight, there were no significant gender differences regarding BDNF plasma levels. However, women displayed significantly lower platelet BDNF levels than men. In addition, platelet BDNF levels changed during the menstrual cycle. In conclusion, we demonstrate that parameters such as age or gender have a specific impact on stored and circulating BDNF levels in peripheral blood.", "author" : [ { "dropping-particle" : "", "family" : "Lommatzsch", "given" : "Marek", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zingler", "given" : "Doerte", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schuhbaeck", "given" : "Katharina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schloetcke", "given" : "Katharina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zingler", "given" : "Christiana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schuff-Werner", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Virchow", "given" : "Johann Christian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurobiology of Aging", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2005", "1", "1" ] ] }, "page" : "115-123", "publisher" : "Elsevier", "title" : "The impact of age, weight and gender on BDNF levels in human platelets and plasma", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1371/journal.pone.0010099", "ISSN" : "1932-6203", "abstract" : "Background Besides its well-established role in nerve cell survival and adaptive plasticity, brain-derived neurotrophic factor (BDNF) is also involved in energy homeostasis and cardiovascular regulation. Although BDNF is present in the systemic circulation, it is unknown whether plasma BDNF correlates with circulating markers of dysregulated metabolism and an adverse cardiovascular profile. Methodology/Principal Findings To determine whether circulating BDNF correlates with indices of metabolic and cardiovascular health, we measured plasma BDNF levels in 496 middle-age and elderly subjects (mean age \u223c70), in the Baltimore Longitudinal Study of Aging. Linear regression analysis revealed that plasma BDNF is associated with risk factors for cardiovascular disease and metabolic syndrome, regardless of age. In females, BDNF was positively correlated with BMI, fat mass, diastolic blood pressure, total cholesterol, and LDL-cholesterol, and inversely correlated with folate. In males, BDNF was positively correlated with diastolic blood pressure, triglycerides, free thiiodo-thyronine (FT3), and bioavailable testosterone, and inversely correlated with sex-hormone binding globulin, and adiponectin. Conclusion/Significance Plasma BDNF significantly correlates with multiple risk factors for metabolic syndrome and cardiovascular dysfunction. Whether BDNF contributes to the pathogenesis of these disorders or functions in adaptive responses to cellular stress (as occurs in the brain) remains to be determined.", "author" : [ { "dropping-particle" : "", "family" : "Golden", "given" : "Erin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emiliano", "given" : "Ana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maudsley", "given" : "Stuart", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Windham", "given" : "B. Gwen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carlson", "given" : "Olga D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Egan", "given" : "Josephine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Driscoll", "given" : "Ira", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferrucci", "given" : "Luigi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "Bronwen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mattson", "given" : "Mark P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Gaetani", "given" : "Silvana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-3", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "4", "9" ] ] }, "page" : "e10099", "publisher" : "Public Library of Science", "title" : "Circulating Brain-Derived Neurotrophic Factor and Indices of Metabolic and Cardiovascular Health: Data from the Baltimore Longitudinal Study of Aging", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1523/JNEUROSCI.6251-09.2010", "ISSN" : "0270-6474", "PMID" : "20392958", "abstract" : "Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain-derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age, and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood.", "author" : [ { "dropping-particle" : "", "family" : "Erickson", "given" : "K. I.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prakash", "given" : "R. S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Voss", "given" : "M. W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaddock", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heo", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McLaren", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pence", "given" : "B. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "S. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vieira", "given" : "V. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Woods", "given" : "J. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McAuley", "given" : "E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kramer", "given" : "A. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neuroscience", "id" : "ITEM-4", "issue" : "15", "issued" : { "date-parts" : [ [ "2010", "4", "14" ] ] }, "page" : "5368-5375", "title" : "Brain-Derived Neurotrophic Factor Is Associated with Age-Related Decline in Hippocampal Volume", "type" : "article-journal", "volume" : "30" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[6,26\u201328]", "plainTextFormattedCitation" : "[6,26\u201328]", "previouslyFormattedCitation" : "[6,26\u201328]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[6,26–28]. There is, however, limited knowledge of BDNF regulation in human brain tissue across ages. We report significant reductions of BDNF exon IV and total long 3’, but not exon I, containing isoforms between the ages of 72 and 104 years old. This corroborates findings from that of Oh and colleagues, who also reported reductions in total and exon IV- containing RNAs in the prefrontal cortex, without any differences in the exon I-containing transcript, between ages 16 to 96 years ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/npp.2016.126", "ISSN" : "0893-133X", "author" : [ { "dropping-particle" : "", "family" : "Oh", "given" : "Hyunjung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lewis", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibille", "given" : "Etienne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychopharmacology", "id" : "ITEM-1", "issue" : "13", "issued" : { "date-parts" : [ [ "2016", "12", "15" ] ] }, "page" : "3080-3091", "title" : "The Role of BDNF in Age-Dependent Changes of Excitatory and Inhibitory Synaptic Markers in the Human Prefrontal Cortex", "type" : "article-journal", "volume" : "41" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[7]", "plainTextFormattedCitation" : "[7]", "previouslyFormattedCitation" : "[7]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[7]. Because only exon IX contains the coding region, all the different exon-containing RNA transcripts will be translated to a single species of BDNF polypeptide. It is hypothesised that this sophisticated gene serves to fine-tune a dynamic transcriptional regulation in different cell types by different neuronal activities. For example, it has been shown in rodent studies that fear conditioning increased both BDNF exon I and IV containing RNA in hippocampus, but only exon IV in the CA1 region ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1523/JNEUROSCI.1786-08.2008", "ISSN" : "0270-6474", "author" : [ { "dropping-particle" : "", "family" : "Lubin", "given" : "F. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roth", "given" : "T. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sweatt", "given" : "J. D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neuroscience", "id" : "ITEM-1", "issue" : "42", "issued" : { "date-parts" : [ [ "2008", "10", "15" ] ] }, "page" : "10576-10586", "title" : "Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Fear Memory", "type" : "article-journal", "volume" : "28" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.4306/pi.2010.7.4.251", "ISSN" : "1738-3684", "PMID" : "21253408", "abstract" : "Neuronal plasticity induced by changes in synaptic morphology and function is well known to play a pivotal role in leaning and memory as well as adaptation to stress. It is suggested that these plastic changes are due to orchestration of alterations in gene expression in the brain. Recent advances in molecular biology have provided evidence that epigenetic mechanisms, such as DNA methylation and histone modification, are crucial to gene transcription in the mammalian brain. Our research group has recently investigated the involvement of histone actylation at the promoter of the brain-derived neurotrophic factor (BDNF) gene in stress-induced reduction in BDNF, as well as in fear conditioning-induced enhancement of BDNF, in the rat hippocampus. The results of the stress study demonstrated that single-immobilization stress significantly reduced the levels of total, exon I, and exon IV BDNF mRNA, and also significantly reduced acetylation levels of histone H3, but not H4, at the promoter of exons I, IV, and VI. The results of the fear conditioning study showed that footshock stress significantly increased the levels of total, exon I, and exon IV BDNF mRNA, with significantly increased acetylation levels of both histone H3 and H4, at the promoter of exons I and IV, followed by enhanced freezing to fear-context exposure. These findings suggest that changes in BDNF transcription in the rat hippocampus in response to stressful stimuli are, at least in part, regulated by histone acetylation status.", "author" : [ { "dropping-particle" : "", "family" : "Fuchikami", "given" : "Manabu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yamamoto", "given" : "Shigeto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morinobu", "given" : "Shigeru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takei", "given" : "Shiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yamawaki", "given" : "Shigeto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychiatry Investigation", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "12" ] ] }, "page" : "251", "title" : "Epigenetic Regulation of <i>BDNF</i> Gene in Response to Stress", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[29,30]", "plainTextFormattedCitation" : "[29,30]", "previouslyFormattedCitation" : "[29,30]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[29,30] while fear memory extinction elevated BDNF exon I and IV in prefrontal cortex ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1101/lm.83304", "ISSN" : "1072-0502", "PMID" : "15537738", "abstract" : "Brain-derived neurotrophic factor (BDNF) has been implicated as a molecular mediator of learning and memory. The BDNF gene contains four differentially regulated promoters that generate four distinct mRNA transcripts, each containing a unique noncoding 5'-exon and a common 3'-coding exon. This study describes novel evidence for the differential usage of alternative BDNF promoters and 5'-exons during the consolidation of learning. We found a selective increase in BDNF transcripts containing exons I and III in the amygdala 2 h following fear conditioning, while mRNA levels of BDNF exons II and IV remained unchanged. These results provide the first evidence of differential splicing and/or differential BDNF promoter usage in response to a behaviorally relevant learning paradigm.", "author" : [ { "dropping-particle" : "", "family" : "Rattiner", "given" : "L. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davis", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ressler", "given" : "Kerry J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Learning & Memory", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2004", "11", "1" ] ] }, "page" : "727-731", "title" : "Differential regulation of brain-derived neurotrophic factor transcripts during the consolidation of fear learning", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[31]", "plainTextFormattedCitation" : "[31]", "previouslyFormattedCitation" : "[31]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[31]. Interestingly, a study on contextual fear conditioning caused a significant increase of BDNF exon I in WT hippocampus while the levels of exon IV remained unchanged ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1124/mol.107.034934", "ISSN" : "0026-895X", "PMID" : "17456785", "abstract" : "We have demonstrated previously that brain-derived neurotrophic factor (BDNF) signaling in the amygdala is required for the consolidation of fear memory. This study is designed to characterize the signal cascades by which fear conditioning modulates transcriptional and translational expression of BDNF. Real-time reverse transcription-coupled polymerase chain reaction showed a significant increase in BDNF exon I- and III-containing mRNA in the amygdala of fear-conditioned rats, indicating that fear conditioning was capable of up-regulating BDNF mRNA. Bilateral administration of actinomycin D or anisomycin to the amygdala attenuated conditioning-induced increase in BDNF protein. Inhibitors for N-methyl-d-aspartate (NMDA) receptor, L-type voltage-dependent calcium channel (L-VDCC), adenylyl cyclase, cAMP-dependent protein kinase (PKA), and calcium/calmodulin-dependent kinase IV (CaMKIV) significantly reduced the increase. Moreover, DNA affinity precipitation and chromatin immunoprecipitation assays showed that phosphorylated cAMP response element-binding protein (p-CREB) binding activity in the proximal region of BDNF promoter I and III was significantly increased after fear conditioning. Intra-amygdala administration of cAMP response element decoy DNA before training impaired fear learning. Taken together, these results suggest that calcium influx through NMDA receptors and L-VDCCs during fear conditioning activates PKA and CaMKIV resulting in CREB phosphorylation. The phosphorylated CREB binds to BDNF promoter and up-regulates the expression of BDNF in the amygdala, which helps the consolidation of fear memory.", "author" : [ { "dropping-particle" : "", "family" : "Ou", "given" : "L.-C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gean", "given" : "P.-W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular Pharmacology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2007", "8", "1" ] ] }, "page" : "350-358", "title" : "Transcriptional Regulation of Brain-Derived Neurotrophic Factor in the Amygdala during Consolidation of Fear Memory", "type" : "article-journal", "volume" : "72" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[32]", "plainTextFormattedCitation" : "[32]", "previouslyFormattedCitation" : "[32]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[32]. This highlights that the different exons can be differently regulated. Mechanistically, within BDNF exon IV promoter three calcium responsive elements (i.e. CaRE1, 2 and 3) have been identified regulating calcium-mediated BDNF IV transcription, while in promoter I there is one CRE in promoter I that can be differently regulated by different Ca2+-stimulated protein kinases and other Ca2+-stimulated intracellular molecules ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1944-8171", "PMID" : "23320132", "abstract" : "Brain-derived neurotrophic factor (BDNF) plays critical roles in many aspects of brain functions, including cell survival, differentiation, development, learning and memory. Aberrant BDNF expression has also been implicated in numerous neurological disorders. Thus, significant effort has been made to understand how BDNF transcription as well as translation is regulated. Interestingly, the BDNF gene structure suggests that multiple promoters control its transcription, leading to the existence of distinct mRNA species. Further, the long- and short-tail of the 3'un-translated region may dictate different sub-cellular BDNF mRNA targeting and translational responses following neuronal stimulation. This review aims to summarize the main findings that demonstrate how neuronal activities specifically up-regulate the transcription and translation of unique BDNF transcripts. We also discuss some of the recent reports that emphasize the epigenetic regulation of BDNF transcription.", "author" : [ { "dropping-particle" : "", "family" : "Zheng", "given" : "Fei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhou", "given" : "Xianju", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moon", "given" : "Changjong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Hongbing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International journal of physiology, pathophysiology and pharmacology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "188-200", "title" : "Regulation of brain-derived neurotrophic factor expression in neurons.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[33]", "plainTextFormattedCitation" : "[33]", "previouslyFormattedCitation" : "[33]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[33]. The calcium hypothesis of aging ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0077-8923", "PMID" : "7847664", "author" : [ { "dropping-particle" : "", "family" : "Khachaturian", "given" : "Z S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the New York Academy of Sciences", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1994", "12", "15" ] ] }, "page" : "1-11", "title" : "Calcium hypothesis of Alzheimer's disease and brain aging.", "type" : "article-journal", "volume" : "747" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0197-4580", "PMID" : "3627349", "abstract" : "This commentary proposes that neurobiology of aging must look beyond the issue of age related changes in calcium concentrations within the cytosol. The more important question is what causes these changes. Studies of structure, function, and dynamics of membranes may begin to give a better clue about underlying mechanisms of these changes.", "author" : [ { "dropping-particle" : "", "family" : "Khachaturian", "given" : "Z S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurobiology of aging", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "0" ] ] }, "page" : "345-6", "title" : "Hypothesis on the regulation of cytosol calcium concentration and the aging brain.", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[34,35]", "plainTextFormattedCitation" : "[34,35]", "previouslyFormattedCitation" : "[34,35]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[34,35], hypothesises a dysregulation of intracellular Ca2+ homeostasis is a primary factor contributing to aging-related learning and memory impairments in humans and other mammals, that may further relate to AD. Perhaps this may reflect differential regulation of BDNF transcritps. Interestingly a NF-kappaB ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-3042", "PMID" : "11461961", "abstract" : "The role of a nuclear factor kappaB (NF-kappaB) in NMDA receptor-mediated neuroprotection is not known. A candidate sequence from the 5' flanking region of exon 3 of the rat brain-derived neurotrophic factor (BDNF) gene was used to show that exposure of rat cerebellar granule cells to 100 microM NMDA activated a specific DNA binding activity that was blocked by the NMDA receptor antagonist MK-801. Anti-p65 antibody or anti-p50 antibody 'supershifted' the DNA binding activity, suggesting that the DNA-protein complex was composed of p65 and p50 subunits. NMDA receptor-mediated neuroprotection was blocked when cerebellar neurons were transfected with a double-stranded oligonucleotide containing the BDNF gene NF-kappaB sequence. Furthermore, nuclear extracts prepared from neurons treated with NMDA and the double-stranded NF-kappaB oligonucleotide showed reduced DNA binding activity to the target sequence, supporting the idea that NF-kappaB may be involved in the transcriptional activation of the BDNF gene. To address this issue, we quantified the level of exon 3-specific BDNF mRNA. Relative to GAPDH mRNA levels and compared with untreated neurons, NMDA increased exon 3-specific BDNF mRNA twofold. In contrast, pretreatment of neurons with the NF-kappaB target DNA abolished the increase in BDNF mRNA following addition of NMDA. We also determined that BDNF itself induced an NF-kappaB DNA binding activity. Taken together, these data support a mechanism where NF-kappaB plays a critical role in NMDA-mediated neuroprotection.", "author" : [ { "dropping-particle" : "", "family" : "Lipsky", "given" : "R H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhu", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kelly", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Terhakopian", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Novelli", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marini", "given" : "A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of neurochemistry", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2001", "7" ] ] }, "page" : "254-64", "title" : "Nuclear factor kappaB is a critical determinant in N-methyl-D-aspartate receptor-mediated neuroprotection.", "type" : "article-journal", "volume" : "78" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[36]", "plainTextFormattedCitation" : "[36]", "previouslyFormattedCitation" : "[36]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[36] site and an E-box ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1523/JNEUROSCI.2262-07.2008", "ISSN" : "1529-2401", "PMID" : "18234890", "abstract" : "Brain-derived neurotrophic factor (BDNF), via activation of TrkB receptors, mediates vital physiological functions in the brain, ranging from neuronal survival to synaptic plasticity, and has been implicated in the pathophysiology of neurodegenerative disorders. Although transcriptional regulation of the BDNF gene (Bdnf) has been extensively studied, much remains to be understood. We discovered a sequence within Bdnf promoter 4 that binds the basic helix-loop-helix protein BHLHB2 and is a target for BHLHB2-mediated transcriptional repression. NMDA receptor activation de-repressed promoter 4-mediated transcription and correlated with reduced occupancy of the promoter by BHLHB2 in cultured hippocampal neurons. Bhlhb2 gene -/- mice showed increased hippocampal exon 4-specific Bdnf mRNA levels compared with +/+ littermates under basal and activity-dependent conditions. Bhlhb2 knock-out mice also showed increased status epilepticus susceptibility, suggesting that BHLHB2 alters neuronal excitability. Together, these results support a role for BHLHB2 as a new modulator of Bdnf transcription and neuronal excitability.", "author" : [ { "dropping-particle" : "", "family" : "Jiang", "given" : "Xueying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tian", "given" : "Feng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Du", "given" : "Yang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Copeland", "given" : "Neal G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jenkins", "given" : "Nancy A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tessarollo", "given" : "Lino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Xuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pan", "given" : "Hongna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hu", "given" : "Xian-Zhang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Ke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kenney", "given" : "Heather", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Egan", "given" : "Sean E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turley", "given" : "Helen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harris", "given" : "Adrian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marini", "given" : "Ann M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lipsky", "given" : "Robert H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of neuroscience : the official journal of the Society for Neuroscience", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2008", "1", "30" ] ] }, "page" : "1118-30", "title" : "BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability.", "type" : "article-journal", "volume" : "28" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[37]", "plainTextFormattedCitation" : "[37]", "previouslyFormattedCitation" : "[37]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[37] have been identified in exon IV promoter that again allow differential regulation and may again reflect age-related changes in these regulatory factors in the brain ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature12143", "ISSN" : "1476-4687", "PMID" : "23636330", "abstract" : "Ageing is a result of gradual and overall functional deteriorations across the body; however, it is unknown whether an individual tissue primarily works to mediate the ageing progress and control lifespan. Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by I\u03baB kinase-\u03b2 (IKK-\u03b2), nuclear factor \u03baB (NF-\u03baB) and related microglia-neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-\u03b2 and NF-\u03baB activation. Mechanistic studies further revealed that IKK-\u03b2 and NF-\u03baB inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. In conclusion, the hypothalamus has a programmatic role in ageing development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.", "author" : [ { "dropping-particle" : "", "family" : "Zhang", "given" : "Guo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Juxue", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Purkayastha", "given" : "Sudarshana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tang", "given" : "Yizhe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Hai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yin", "given" : "Ye", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Bo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Gang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cai", "given" : "Dongsheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7448", "issued" : { "date-parts" : [ [ "2013", "5", "9" ] ] }, "page" : "211-6", "title" : "Hypothalamic programming of systemic ageing involving IKK-\u03b2, NF-\u03baB and GnRH.", "type" : "article-journal", "volume" : "497" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[38]", "plainTextFormattedCitation" : "[38]", "previouslyFormattedCitation" : "[38]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[38](Zhang et al).We report variant-specific associations with the rs6265 variant. Specifically, Met-carriers had an upregulation of BDNF transcripts containing exon IV, but not exon I or total long 3’UTR transcripts, compared to Val-homozygotes. The effect of the rs6265 polymorphism on BDNF gene expression is largely unknown ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3389/fnmol.2018.00156", "ISSN" : "1662-5099", "abstract" : "Neurotrophins have been implicated in the pathophysiology of many neuropsychiatric diseases. Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain. Its Val66Met polymorphism (rs6265) is a common and functional single-nucleotide polymorphism (SNP) affecting the activity-dependent release of BDNF. Considering the important role of BDNF in brain function, more than 1,100 genetic studies have investigated this polymorphism. Although these studies have reported some encouraging positive findings initially, most of the findings cannot be replicated in following studies. These inconsistencies in BDNF Val66Met genetic studies may be attributed to many factors such as age, sex, environmental factors, ethnicity, genetic model used for analysis, and gene\u2013gene interaction, which are discussed in this review. We also discuss the results of recent studies that have reported the novel functions of this polymorphism. Because many BDNF polymorphisms and nongenetic factors have been implicated in the complex traits of neuropsychiatric diseases, future studies should apply data mining and machine learning techniques to determine the genetic role of BDNF in neuropsychiatric diseases.", "author" : [ { "dropping-particle" : "", "family" : "Tsai", "given" : "Shih-Jen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Frontiers in Molecular Neuroscience", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2018", "5", "15" ] ] }, "page" : "156", "publisher" : "Frontiers", "title" : "Critical Issues in BDNF Val66Met Genetic Studies of Neuropsychiatric Disorders", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[39]", "plainTextFormattedCitation" : "[39]", "previouslyFormattedCitation" : "[39]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[39]. A previous study involving over 500 prefrontal cortex donor samples revealed no differences of BDNF gene expression between rs6265 genotypes ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1212/WNL.0000000000002387", "ISSN" : "0028-3878", "PMID" : "26819457", "abstract" : "OBJECTIVES We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults. METHODS Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression. RESULTS Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in individuals with pathologic AD (p = 0.006), but was not associated with macroscopic infarcts, Lewy body disease, or hippocampal sclerosis. BDNF expression remained associated with cognitive decline in a model adjusting for age, sex, education, and neuropathologies (p < 0.001). Furthermore, the effect of AD pathology on cognitive decline varied by BDNF expression such that the effect was strongest for high levels of AD pathology (p = 0.015); thus, in individuals with high AD pathology (90th percentile), cognitive decline was about 40% slower with the 90th percentile BDNF expression vs 10th. CONCLUSIONS Higher brain BDNF expression is associated with slower cognitive decline and may also reduce the deleterious effects of AD pathology on cognitive decline.", "author" : [ { "dropping-particle" : "", "family" : "Buchman", "given" : "Aron S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yu", "given" : "Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boyle", "given" : "Patricia A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schneider", "given" : "Julie A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jager", "given" : "Philip L.", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bennett", "given" : "David A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurology", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2016", "2", "23" ] ] }, "page" : "735-741", "title" : "Higher brain <i>BDNF</i> gene expression is associated with slower cognitive decline in older adults", "type" : "article-journal", "volume" : "86" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[40]", "plainTextFormattedCitation" : "[40]", "previouslyFormattedCitation" : "[40]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[40]. Despite the superior statistical power in this analysis, expression levels of different transcript variants were not reported, rather, only total expression. Given our preliminary insight suggesting the influence of the rs6265 variant may be transcript-specific in BDNF expression, it would be interesting to replicate our analysis in this population.The reduction in BDNF expression with AD neuropathology is in agreement with other reports analysing prefrontal ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1212/WNL.0000000000002387", "ISSN" : "0028-3878", "PMID" : "26819457", "abstract" : "OBJECTIVES We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults. METHODS Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression. RESULTS Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in individuals with pathologic AD (p = 0.006), but was not associated with macroscopic infarcts, Lewy body disease, or hippocampal sclerosis. BDNF expression remained associated with cognitive decline in a model adjusting for age, sex, education, and neuropathologies (p < 0.001). Furthermore, the effect of AD pathology on cognitive decline varied by BDNF expression such that the effect was strongest for high levels of AD pathology (p = 0.015); thus, in individuals with high AD pathology (90th percentile), cognitive decline was about 40% slower with the 90th percentile BDNF expression vs 10th. 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Our results clarified the available controversies regarding the role of rs6265 in AD and indicated that BDNF may be a female-specific risk gene for AD.", "author" : [ { "dropping-particle" : "", "family" : "Li", "given" : "Guo-Dong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bi", "given" : "Rui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Deng-Feng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Min", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Rongcan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Dong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fang", "given" : "Yiru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Tao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Chen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yao", "given" : "Yong-Gang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurobiology of Aging", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2017", "5", "1" ] ] }, "page" : "192.e11-192.e19", "publisher" : "Elsevier", "title" : "Female-specific effect of the BDNF gene on Alzheimer's disease", "type" : "article-journal", "volume" : "53" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[41]", "plainTextFormattedCitation" : "[41]", "previouslyFormattedCitation" : "[41]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[41]. Interestingly, our results further suggest the association between expressions and neuropathology magnitude may be stage specific. Specifically, those with early AD neuropathology having significant BDNF downregulation seem to be particularly affected. Increased neuroinflammation is suspected to have a major role in AD progression. The predominant hypothesis suggests levels of neuroinflammation peaks early on, possibly reflecting an initial anti-inflammatory response, followed by a second peak during conversion from MCI to AD, which may indicate a pro-inflammatory shift ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jalz.2016.02.010", "ISSN" : "15525260", "PMID" : "27179961", "abstract" : "Several attempts have been made to treat Alzheimer's disease (AD) using anti-amyloid strategies with disappointing results. It is clear that the \"amyloid cascade hypothesis\" alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies. Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful. In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression. We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro-inflammatory factors, and neuronal damage. We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target.", "author" : [ { "dropping-particle" : "", "family" : "Calsolaro", "given" : "Valeria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Edison", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Alzheimer's & Dementia", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2016", "6" ] ] }, "page" : "719-732", "title" : "Neuroinflammation in Alzheimer's disease: Current evidence and future\u00a0directions", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.jalz.2014.06.016", "ISSN" : "15525260", "PMID" : "25239737", "abstract" : "BACKGROUND Alzheimer's disease (AD) and Parkinson's disease (PD) are the two common neurodegenerative diseases characterized by progressive neuronal dysfunction in the presence of pathological microglial activation. METHODS 10 AD, 10 mild cognitive impairment (MCI), 11 PD dementia (PDD), and 16 controls underwent magnetic resonance imaging, [11C](R)PK11195 (1-[2-chlorophenyl]-N-methyl-N-[1-methyl-propyl]-3-isoquinoline carboxamide), [11C]PIB (11C-Pittsburgh compound B), [18F]FDG-PET (18F-2-fluoro-2-deoxyglucose positron emission tomography) scans. Parametric images were interrogated using region of interest (ROI), biological parametric mapping (BPM) and statistical parametric mapping analysis, and neuropsychometric tests. RESULTS Using BPM analysis, AD, MCI, and PDD subjects demonstrated significant correlation between increased microglial activation and reduced glucose metabolism (rCMRGlc). AD and MCI subjects also showed significant positive correlation between amyloid and microglial activation. Levels of cortical microglial activation were negatively correlated with Mini-Mental State Examination in both AD and PDD. CONCLUSION The significant inverse correlations between cortical levels of microglial activation and rCMRGlc in AD and PDD suggest cortical neuroinflammation may drive neuronal dysfunction in these dementias.", "author" : [ { "dropping-particle" : "", "family" : "Fan", "given" : "Zhen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aman", "given" : "Yahyah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ahmed", "given" : "Imtiaz", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chetelat", "given" : "Ga\u00ebl", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Landeau", "given" : "Brigitte", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ray Chaudhuri", "given" : "K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brooks", "given" : "David J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Edison", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Alzheimer's & Dementia", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2015", "6" ] ] }, "page" : "608-621.e7", "title" : "Influence of microglial activation on neuronal function in Alzheimer's and Parkinson's disease dementia", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[43,44]", "plainTextFormattedCitation" : "[43,44]", "previouslyFormattedCitation" : "[43,44]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[43,44]. This complex relationship may be related to the microglial reaction following the deposition and propagation of amyloid and hyperphosphorylated tau pathologies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3233/JAD-131843", "ISSN" : "1875-8908", "PMID" : "23948931", "abstract" : "Neuroinflammation is a process related to the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Increasing sets of evidence support the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration, a process we are calling neuroimmunomodulation in AD. On the basis of the hypothesis that pathological tau aggregates induce microglial activation with the subsequent events of the neuroinflammatory cascade, we have studied the effects of tau oligomeric species and filamentous structures over microglial cells in vitro. Tau oligomers and fibrils were induced by arachidonic acid and then their actions assayed upon addition to microglial cells. We showed activation of the microglia, with significant morphological alterations as analyzed by immunofluorescence. The augmentation of nitrites and the proinflammatory cytokine IL-6 was evaluated in ELISA assays. Furthermore, conditioned media of stimulated microglia cells were exposed to hippocampal neurons generating altered patterns in these cells, including shortening of neuritic processes and cytoskeleton reorganization.", "author" : [ { "dropping-particle" : "", "family" : "Morales", "given" : "Inelia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jim\u00e9nez", "given" : "Jos\u00e9 M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mancilla", "given" : "Marcela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maccioni", "given" : "Ricardo B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Alzheimer's disease : JAD", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "10", "10" ] ] }, "page" : "849-56", "title" : "Tau oligomers and fibrils induce activation of microglial cells.", "type" : "article-journal", "volume" : "37" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[45]", "plainTextFormattedCitation" : "[45]", "previouslyFormattedCitation" : "[45]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[45]. Numerous studies demonstrate that neuroinflammation in turn affects the expression of BDNF within the brain; therefore, reduction of BDNF expression and function may be a key mechanism underlying the negative impact of pro-inflammatory cytokines on neuroplasticity ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3389/fncel.2014.00430", "ISSN" : "1662-5102", "author" : [ { "dropping-particle" : "", "family" : "Calabrese", "given" : "Francesca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossetti", "given" : "Andrea C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Racagni", "given" : "Giorgio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gass", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riva", "given" : "Marco A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Molteni", "given" : "Raffaella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Frontiers in Cellular Neuroscience", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "12", "22" ] ] }, "title" : "Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[46]", "plainTextFormattedCitation" : "[46]", "previouslyFormattedCitation" : "[46]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[46].There are a number of limitations to this study. Variations in postmortem times and RIN values (Supplementary Table 1) impacted some of the results such as BDNF promoter I methylation and exon I-containing transcript expression, that when we adjusted for, significance was lost. Also, some RNA samples were unable to clearly measured for all transcripts from the total 67 subjects (i.e. exon I, n=53; exon IV, n=64; long 3’UTR, n=66). A further confounding variable is that the prefrontal cortex samples also contain relatively heterogeneous cell populations that were not able to control for. Finally, we only investigated specific promoters and transcripts containing exon I, IV and long 3’UTR, though it would be interesting to investigate further regions of the BDNF gene and more complete coverage of all the different transcripts.ConclusionIn conclusion, we report prefrontal cortex BDNF gene expression is associated with ageing, rs6265 carrier status and AD neuropathology in a variant-specific manner. This dysregulation seems to be independent of DNA methylation influences at the I and IV promoters. These results add further evidence to the complex regulation of the BDNF gene within the cortex.Conflict of interest / Disclosure statementThe authors have no conflict of interests to report.ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY [1] Kang H, Schuman EM (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267, 1658–62.[2] Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709.[3] McKinney BC, Lin C-W, Oh H, Tseng GC, Lewis DA, Sibille E (2015) Hypermethylation of BDNF and SST Genes in the Orbital Frontal Cortex of Older Individuals: A Putative Mechanism for Declining Gene Expression with Age. 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Neurochem. 82, 1058–1064.[43] Calsolaro V, Edison P (2016) Neuroinflammation in Alzheimer’s disease: Current evidence and future?directions. Alzheimer’s Dement. 12, 719–732.[44] Fan Z, Aman Y, Ahmed I, Chetelat G, Landeau B, Ray Chaudhuri K, Brooks DJ, Edison P (2015) Influence of microglial activation on neuronal function in Alzheimer’s and Parkinson's disease dementia. Alzheimer’s Dement. 11, 608–621.e7.[45] Morales I, Jiménez JM, Mancilla M, Maccioni RB (2013) Tau oligomers and fibrils induce activation of microglial cells. J. Alzheimers. Dis. 37, 849–56.[46] Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R (2014) Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front. Cell. Neurosci. 8,.FiguresFigure 1. Associations between donor age at death with A: BDNF I variant, B: BDNF IV variant and C: BDNF total mRNA expression.Figure 2. Difference in BDNF gene expression between rs6265 Val-homozygotes and Met-carriers. BDNF I: Val-homozygotes N = 28, Met-carriers N = 25. BDNF IV: Val-homozygotes N = 37, Met-carriers N = 27. BDNF total long 3’UTR: Val-homozygotes N = 38, Met-carriers N = 28 * P < 0.05.Figure 3. Difference in BDNF total long 3’variant gene expression between AD neuropathology groups. N = 16 (Not), 14 (Low), 26 (Intermediate), 5 (High). * P < 0.05. Supplementary Figure 1. Schematic of the Human BDNF gene. Untranslated first exons are numbered I – VIII and the coding sequence for pro-BDNF is shaded black. Sequences of regions of promoters I and IV investigated for DNA methylation [Exon I, chr11:27,722,265-27,722,319; Exon IV, chr11:27,701,578-27,701,672 (Hg38)] are shown with CpG residues in bold.Supplemental Table 1. Sample details.Patient_CodeAge_at_deathGenderBrain_Weight (g)PMDSmoker (S), Drinker(D)Primary_Pathology_Diagnosis_DescriptionRIN_Value2270891F1216.00133.0S2, D3Age changes only3.201105294F946.00111.0S1, D3Age changes only5.301054098F1029.0084.0S1, D2Possible AD6.1011383100F1058.0061.5S1, D3CAA4.602133786F1334.0096.0S3, D3AD6.101228496F-154.0S2 D1Moderate AD pathology2.301106083F1108.0094.0S2,D3Mild AD changes in temporal lobe2.301129989M1070.0036.0S2,D2Age-related tau astrogliopathy with hippocampal sclerosis and secondary TDP-434.902262591M1157.0093.0S2,D3Age changes only4.001019297M1252.00120.5S1,D2Argyrophilic Grain Disease with v.mild AD-like tau2.602027494F1166.0086.0S2,D3Early/Incipient AD2.801161879F-116.0S2,D2Argyrophilic Grain Disease3.401050281F1160.00113.5S3,D3Probable AD5.301054489F1450.00144.0S2,D3CAA (?)moderate SVD2.901197181F1363.0044.0S1,D2Early/incipient AD4.502309676F1204.0047.0S1,D2Mild AD changes in temporal lobe2.302209182F1020.0061.0S1,D3Age changes only2.701276290F1217.00103.0S1,D2Age changes only4.402210589M-128.0S1,D3Incipient AD5.601250490M-156.0S2,D2Age changes only#NULL!10640104F1289.0078.0S2,D3AD3.102219488F1129.004.0S1,D1Early limbic predominant DLB5.902286793F1133.0070.5S1,D3Probable AD2.502129785M-187.5S2,D3Mild CAA4.202008890F-41.5S1,D2Age changes only2.302117986M1100.0026.0S2,D3AD2.301184589F-36.0S1,D2CVD2.302168390F1050.0039.0S2,D3Age changes only6.302234076F1359.00129.5S1,D3Age changes only6.501269887F-39.0S2,D2Age changes only5.801124089M-27.0S1,D3Age changes only3.301137980F1000.0081.0S1,D1Probable AD4.602084595F1116.0088.0S1,D1Possible AD3.402211085M-12.0S3,D3Age changes only5.002149391M--S2,D3Moderate SVD3.302109287F1152.0024.0S3,D3Age changes only2.501166281F1250.00-S2,D3Incipient AD2.301071972F1230.00-S3,D3Incipient AD2.602042992M-24.0S2,D3Moderate CVD3.401180289F-134.0S1,D2Mild AD pathology5.101117682F1174.0046.0S3,D1Mild DLB4.501142778M-144.0S2,D3Age changes only5.701155094M1550.0042.0S1,D1CAA?6.802042882F-96.0S1,D3Probable AD3.201134192M1270.0048.0S2,D3Early/incipient AD2.902269179F1290.00-S1,D3Incipient AD2.302208387M-120.0S2,D3Mild AD2.452040289F-72.0S1,D3AD4.502038278F--S3,D2Probable AD2.501150894F1150.00-S1,D3Age changes only3.401000486M-18.0S1,D3DLB2.701275589F1351.0056.0S2,D3Moderate AD pathology2.602227293M1348.0039.0S2,D3Mild transitional DLB2.302273888F-72.0S2,D3Mild CVD2.701202282F1210.00120.0S2,D3Mild AD/PD path.2.201066490M1134.00114.5S2,D3Corticobasal degeneration4.801203391M1520.0043.5S2,D3Mild SVD4.001077287F1019.0060.0S3,D3AD3.102093592F-37.0S2,D3Age changes only2.401013281F1210.0041.0S3,D2Age changes only3.501222187M1410.0080.0S2,D3CVD2.402166490F-6.0S1,D3Possible AD2.401011887F1178.0087.0S3,D3Mild AD path. in temporal lobe4.701142688F-72.0S3,D3AD2.601241380M1240.00-S2,D3Incipient AD2.201132287F1305.00120.0S1,D3PD6.501095485F-12.0S2,D2Mild CAA2.50Alzheimers Disease, AD; Parkinsons Disease, PD; cerebral amyloid angiopathy, CAA; cerebrovascular disease, CVD; Smoker (S;1 never; 2 ex-smoker; 3 current) Drinker (D never; 2 ex-smoker; 3 current); Supplemental Table 2. Pearson correlations between BDNF gene expression, methylation and protein with RIN and PMD timesCorrelationsLgBDNF_Transcript1_Exp_NewLgBDNF_Transcript4_Exp_NewLgBDNF_Total_Exp_NewLgMeth_PromI_AvgLgMeth_PromIV_AvgLgBDNFproteinRNA RIN ValuePostmortum delay (hours)LgBDNF_Transcript1_Exp_NewPearson Correlation1.608**.371**-.268-.124.272-.058.037Sig. (2-tailed).000.006.054.378.051.678.799N5353535253525349LgBDNF_Transcript4_Exp_NewPearson Correlation.608**1-.106-.162-.038.058.244-.066Sig. (2-tailed).000.406.205.768.652.052.626N5364646364626457LgBDNF_Total_Exp_NewPearson Correlation.371**-.1061-.179-.069.101-.475**-.043Sig. (2-tailed).006.406.153.585.427.000.746N5364666565646659LgMeth_PromI_AvgPearson Correlation-.268-.162-.1791.102.078.026-.144Sig. (2-tailed).054.205.153.418.539.836.277N5263656665646559LgMeth_PromIV_AvgPearson Correlation-.124-.038-.069.1021.018.025-.303*Sig. (2-tailed).378.768.585.418.889.845.020N5364656566646559LgBDNFproteinPearson Correlation.272.058.101.078.0181-.047.272*Sig. (2-tailed).051.652.427.539.889.710.039N5262646464656458RNA RIN ValuePearson Correlation-.058.244-.475**.026.025-.0471.166Sig. (2-tailed).678.052.000.836.845.710.209N5364666565646659Postmortum delay (hours)Pearson Correlation.037-.066-.043-.144-.303*.272*.1661Sig. (2-tailed).799.626.746.277.020.039.209N4957595959585960**. Correlation is significant at the 0.01 level (2-tailed).*. Correlation is significant at the 0.05 level (2-tailed).Supplemental Table 3. Partial correlation matrix, controlling for donor ages and RIN values, between BDNF gene expression, DNA methylation and protein levelsCorrelationsControl VariablesLgBDNF_Transcript1_Exp_NewLgBDNF_Transcript4_Exp_NewLgBDNF_Total_Exp_NewLgMeth_PromI_AvgLgMeth_PromIV_AvgLgBDNFproteinRNA RIN Value & Age at deathLgBDNF_Transcript1_Exp_NewCorrelation1.000.596.301-.253-.090.266Significance (2-tailed)..000.035.080.539.065df04747474747LgBDNF_Transcript4_Exp_NewCorrelation.5961.000.149-.137.034.039Significance (2-tailed).000..306.347.818.790df47047474747LgBDNF_Total_Exp_NewCorrelation.301.1491.000-.297-.144.146Significance (2-tailed).035.306..038.323.317df47470474747LgMeth_PromI_AvgCorrelation-.253-.137-.2971.000.212.093Significance (2-tailed).080.347.038..143.525df47474704747LgMeth_PromIV_AvgCorrelation-.090.034-.144.2121.000-.006Significance (2-tailed).539.818.323.143..970df47474747047LgBDNFproteinCorrelation.266.039.146.093-.0061.000Significance (2-tailed).065.790.317.525.970.df47474747470 ................
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