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Sci Rep. 2016 Sep 29;6:34051. doi: 10.1038/srep34051.

Rescue of Early bace-1 and Global DNA Demethylation by S-Adenosylmethionine Reduces Amyloid Pathology and Improves Cognition in an Alzheimer's Model.

Author information

1
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
2
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
3
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
4
Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.
5
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Abstract

General DNA hypomethylation is associated with Alzheimer's disease (AD), but it is unclear when DNA hypomethylation starts or plays a role in AD pathology or whether DNA re-methylation would rescue early amyloid-related cognitive impairments. In an APP transgenic mouse model of AD-like amyloid pathology we found that early intraneuronal amyloid beta build-up is sufficient to unleash a global and beta-site amyloid precursor protein cleaving enzyme 1 (bace-1) DNA demethylation in AD-vulnerable brain regions. S-adenosylmethionine administration at these early stages abolished this hypomethylation, diminished the amyloid pathology and restored cognitive capabilities. To assess a possible human significance of findings, we examined the methylation at 12 CpGs sites in the bace-1 promoter, using genome-wide DNA methylation data from 740 postmortem human brains. Thus, we found significant associations of bace-1 promoter methylation with β-amyloid load among persons with AD dementia, and PHFtau tangle density. Our results support a plausible causal role for the earliest amyloid beta accumulation to provoke DNA hypomethylation, influencing AD pathological outcomes.

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