Studies on DNA methylation (DNAm) in Alzheimer's disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression. Here, we conducted an epigenome-wide association study (EWAS) using DNAm profiles in entorhinal cortex (EC) from 149 AD patients and control brains and combined these with two previously published EC datasets by meta-analysis (total n=337). We identified 12 cytosine-phosphate-guanine (CpG) sites showing epigenome-wide significant association with either case-control status or Braak's tau-staging. Four of these CpGs, located in proximity to TENT5A, PALD1, PRF1, and DIRAS1, were not reported previously. Integrating DNAm levels with RNA sequencing-based mRNA expression data generated in the same individuals showed significant DNAm-mRNA correlations for 6 of the 12 significant CpGs. By calculating rates of epigenetic age acceleration using two recently proposed "epigenetic clock" estimators we found a significant association with accelerated epigenetic aging in AD patients vs. controls. In summary, our study represents the hitherto most comprehensive EWAS in AD using EC and highlights several novel differentially methylated loci with potential effects on gene expression.
Background: Dysregulation of microRNAs (miRNAs) is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer′s disease (AD). Hitherto, sample sizes from differential miRNA expression studies in AD are exceedingly small aggravating any biological inference. To overcome this limitation, we investigated candidate miRNAs previously showing compelling evidence in the literature in a large collection of brain samples from AD and control individuals. Methods: Brain tissue was derived from superior temporal gyrus (STG) and entorhinal cortex (EC) from 100 AD patients and 99 control individuals. Expression of six selected miRNAs was assessed either by qPCR (STG) or small RNA sequencing (EC). Brain region-dependent differential miRNA expression was assessed in a transgenic AD mouse model. All results were combined with those from other datasets by meta-analysis. Results: MiR-129-5p, miR-132-5p, and miR-138-5p were significantly downregulated in AD vs. controls both in STG and EC. In contrast, we found no strong evidence for differential miRNA expression for miR-125b-5p and miR-501-3p, which previously ranked high by meta-analysis. In addition, we observed miR-195-5p to be significantly upregulated in EC of AD, but not in STG. The brain region-specific nature of differential miR-195-5p expression was corroborated by targeted qPCR analyses in an AD transgenic mouse model. Conclusions: Using two different methods (qPCR and small RNA-seq) in two separate brain regions in ≈200 AD patients and controls we more than doubled the available sample size for most miRNAs tested. Differential miRNA expression analyses confirm the likely involvement of miR-129-5p, miR-132-5p, miR-138-5p, and miR-195-5p in AD pathogenesis.
Alzheimer disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.
Prion diseases are a group of etiologically heterogeneous neurodegenerative disorders. We have analyzed the coding region of PRNP gene in 121 healthy citizens of Serbia to determine whether the frequencies of M129V, E219K, and octapeptide repeat number polymorphism. For Serbian population, polymorphism of PRNP gene at codon 129 does not differ from healthy European populations. Also codon 219 is monomorphic for the Glu allele both in Serbian population and other European populations. On the contrary, in Serbian population we did not detect any deletions or insertions in octapeptide repeat region, whereas deletions were detected in other European populations.
Background: Epigenetic changes of the FKBP5 locus in adults were reported to be allele specific and trauma related in different patient populations. However, DNA methylation status of FKBP5 and its relation to the circulating protein levels are still unknown in schizophrenia spectrum disorders. Methods: This pilot study of homogeneous sample from Serbia included 24 patients and 24 age-(29.6 ± 5.8 and 30.8 ± 7.0 years) and sex-(male 54.2% and 45.8%, respectively) matched healthy controls. Trauma was assessed by Childhood Trauma Questionnaire (CTQ). DNA methylation level of FKBP5 in intron 7 was analyzed by bisulfite conversion, followed by Sanger sequencing. Additionally, functional FKBP5 genetic variant rs1360780 was genotyped. Levels of FK506-binding protein 5 were measured from peripheral blood mononuclear cells using Western blot. To explore effects of CTQ and rs1360780 on the methylation scores and effects of DNA methylation on circulating protein levels we used linear regression analyses. Results: The patients had more early-life trauma than controls (P = .03) and higher frequency of risk (T) genotype (82.6% and 56.5%, respectively, P = .055). Subjects with psychosis had FKBP5 demethylation in each of the CpG sites (P < .05). Exposure to trauma predicted levels of FKBP5 methylation in healthy controls (at CpG3 site and in the average methylation level of the observed region, R 2 = .337, β = −0.581, P = .006 and R 2 = .372, β = −.610, P = .003, respectively). In patients, CTQ predicted demethylation only on the CpG2 site (R 2 = .155, β = .394) and with borderline significance (P = .095). After FKBP5 methylation levels were set as independent variables and levels of the protein as an outcome, different patterns were observed in patients and controls. FKBP5 demethylation significantly predicted higher FKBP5 protein levels only in patients (R 2 = .533, β = −.730, P = .000). Overall, methylation status of CpG2 site was significant predictor of the protein levels only in risk allele carriers (R 2 = .596, β = −.765, P < .001), suggesting that observed associations between the DNA methylation and FKBP5 protein levels were genotype dependent. Conclusion: Termination of the stress response after the end of a threat depends on glucocorticoid receptor complex and stress hormone system. FKBP5 is an important functional regulator of the glucocorticoid receptor complex and this preliminary results contribute towards better understanding of its alterations in psychosis. GLUCOCORTICOID-MEDIATED EPIGENETIC CONTROL OF DOPAMINERGIC NEURONS IN A TRAJECTORY FROM ADOLESCENT STRESS TO ADULT BEHAVIORMinae Niwa*, and Akira Sawa Johns Hopkins University School of Medicine Background: Psychosocial stress during adolescence may affect the trajectory of brain maturation and facilitate the onset of major mental illness after puberty, especially when combined with mild perturbations in early development. However, the key question of how aberrant neuronal maturation during adolescence may contribute to the disease onset has not been fully ...
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