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DNA methylation profiling of neuron and glia for the dissection of cell type, age and Alzheimer’s disease-specific changes in the human brain

ABSTRACT: Alzheimer’s disease (AD) is a progressive brain disorder caused by altered neuronal and glial cell functions. Illumina 450K profiling of cells (nuclei) sorted from post- mortem human brains allowed us assigning cell type- specific epigenetic changes to aging and AD progression. Among a few thousand cell type-specific differentially methylated CpGs (DMCGs) changing with age we identify prominent clusters in the AD genes, CLU, SYNJ2, ANK1 and MCF2L. A distinct set of age independent AD-specific DMCGs shows strong cell specific changes in the genes TOLLIP, BACE2, PKAR1B, PDE9A, ROBO2, FERMT2, UGT8, SPON1, INPP5D, LNFG and SRPK2. Some AD-specific DMCGs even reveal incremental changes with advancing BRAAK stages. In summary we observe a striking presence of DMCGs in major LOAD genes establishing novel connections between genetic and epigenetic contributions to AD. In addition the cell-specific association allows to functionally discriminate epigenetic effects of aging from those related to AD in the human brain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66351 | GEO | 2018/08/12

REPOSITORIES: GEO

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Project description:Many forms of synaptic plasticity are critically dependent upon production of cGMP to trigger activity-dependent increases in synaptic size and strength. Phosphodiesterase 9A (PDE9A) is a high affinity, cGMP-specific phosphodiesterase with widespread distribution in the central nervous system. Inhibition of PDE9A results in significant accumulation of cGMP in brain tissue and cerebrospinal fluid (CSF) of rodents, and increases CSF cGMP in human volunteers. We hypothesized that chronic exposure to a PDE9A inhibitor, and the associated elevations in brain cGMP could provide a therapeutic benefit to vulnerable synapses chronically exposed to Aβ in transgenic mice over-expressing human mutant amyloid precursor protein (Tg2576 mice). A total of N=20 animals per group of 4 month old Tg2576 mice and non-transgenic littermates (WT) were implanted with Alzet osmotic minipumps to deliver vehicle or the PDE9A inhibitor PF-04447943. Neurobehavioral outcomes were measured as conditioned fear response after 28 days of treatment and subsequently brains were harvested for measurement of Aβ, gene expression profiling or synaptic density as assessed by Golgi staining of dendrites. Dendritic spine density on apical dendrites of CA1 neurons exhibited a small but significant deficit in the density of dendritic spines in vehicle treated Tg2576 mice as compared to WT mice. This deficit was ameliorated by 30 days of exposure to PF-04447943. No significant drug effect was observed in WT mice. No significant effects of drug treatment were observed on Aβ levels in Tg2576 mice. Behavioral analysis of Tg2576 mice showed deficits in fear conditioning as early as 2 months old, and therefore were considered unlikely to be due to the accumulation of oligomeric Aβ. These deficits were not affected by drug treatment. Transcriptional profiles of Tg2576 mice treated with drug compared to vehicle showed evidence of regulation of pathways related to synaptic plasticity and remodeling of the dendritic cytoskeleton, consistent with stabilization of vulnerable spine structure. These data supports the hypothesis that PDE9A inhibition can stabilize vulnerable synapses early in the Alzheimer’s disease process. 4-month old Tg2576 mice and non-transgenic (WT) littermates were implanted with minipumps to deliver vehicle or the PDE9A-inhibitor, PF-04447943, for 28 days. At the end of the study, hippocampus and frontal cortex were dissected from n=8 mice per group, RNA was isolated, and hybridized to Affymetrix 430 2.0 mouse whole genome microarray.

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DNA methylation profiling of neuron and glia for the dissection of cell type, age and Alzheimer’s disease-specific changes in the human brain

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