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Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease [ChIP-Seq]

ABSTRACT: Aging is the strongest risk factor for Alzheimer's disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compared the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We find that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes having distinctive functional roles. Furthermore, we discover an association between the genomic locations of significant H4K16ac changes with genetic variants (SNPs) identified in prior AD genome-wide association studies (GWAS) and with expression quantitative trait loci (eQTLs). Our results establish the basis for an epigenetic link between aging and AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84618 | GEO | 2018/03/07

REPOSITORIES: GEO

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Project description:Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer’s disease (AD), however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively-intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with Aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59 yrs), cognitively-intact aging (73-95 yrs) and age-matched AD cases. To identify “anti-Aging/AD” transcription patterns associated with physical activity, probesets significantly associated with both physical activity and Aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2138 probesets significant in both datasets, nearly 95% showed opposite transcription patterns with physical activity compared to Aging/AD. The majority (>70%) of these anti-Aging/AD genes showed increased expression with physical activity and decreased expression in Aging/AD. Enrichment analysis of the anti-Aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling and synaptic spine plasticity. Anti-Aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function. These data suggest that physical activity preserves a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.

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Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease [ChIP-Seq]

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