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Observing epigenetic changes in cells is to observe their reactions to circumstances, as epigenetic mechanisms determine the timing and amount of proteins produced from their genetic blueprints. Protein levels are the switches and dials of the machinery of the cell, determining behavior. These epigenetic changes have consequences, but it is important to remember that they are not root causes. They are a middle portion in a longer process, and thus most likely not the best place to intervene. The present state of technology makes it much easier to examine epigenetic changes than to trace back to root causes, unfortunately, which might tend to bias the medical development emerging from the research community towards less useful approaches.
The primary neuropathological signs of Alzheimer’s disease (AD) are intraneuronal neurofibrillary tangles and extracellular β-amyloid (Aβ) plaques, along with accompanying synaptic and neuronal loss. In general, the distribution of neurofibrillary tangles in the AD brain follows a stereotypic pattern; beginning in the entorhinal/perirhinal cortex, progressing to limbic structures including the hippocampus, and then finally spreading neocortically across the frontal, temporal, and parietal cortex. Loss of neurons and severity of cognitive impairments in AD correspond closely with the burden of tangle pathology.
The neurodegenerative process is also mediated by excessive production and accumulation of Aβ peptides forming plaques. Generation of pathogenic Aβ peptides requires β-secretase (BACE1), which cleaves amyloid precursor protein (APP); the rate-limiting step in Aβ production. Synaptic dysfunction in AD, which is evident long before substantial neuronal loss, has been attributed to elevated BACE1 levels prompting the overproduction of toxic Aβ at synaptic terminals. Recently, it has been demonstrated that Aβ plaques create an environment that enhances the aggregation of tau, which in turn forms intracellular neurofibrillary tangles. Consequently, Aβ and neurofibrillary tangles jointly cooperate in the progression of AD. However, AD is not a normal part of aging and the biological mechanisms causing some individuals, but not others, to develop disease pathology remain unclear.
Epigenetic mechanisms could contribute to AD, as many manifestations of aging, including age-dependent diseases, have an epigenetic basis. Epigenetic marks like DNA methylation regulate gene transcription, are responsive to environmental changes, and show widespread remodeling during aging. Enhancers are genomic elements that modulate the complex spatial and temporal expression of genes, and are subject to epigenetic regulation. Prior genome-wide studies examining DNA methylation changes in the AD brain report a significant overlap between differential methylation and enhancer elements, suggesting that epigenetic disruption of enhancer function contributes to AD. Hence, in this study we perform a genome-wide analysis of DNA methylation at enhancers in neurons from AD brain.
We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated in AD neurons. Methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.