Chronic hypoxia facilitates Alzheimer's disease through demethylation of γ-secretase by downregulating DNA methyltransferase 3b

Introduction Environmental factors and epigenetic mechanisms are believed to contribute to Alzheimer's disease (AD). We previously documented that prenatal hypoxia aggravated the cognitive impairment and neuropathology in offspring mice. Here, we investigate the chronic hypoxia-induced epigenetic modifications in AD. Methods The 3-month-old APP^swe/PS1^dE9 mice were exposed to hypoxic environment 6 hour/day for 30 days, followed by learning and memory tests and biochemical and neuropathology measurement at the age of 4, 6, and 9 months. Results We found hypoxia exaggerated the neuropathology and cognitive impairment in AD mice. Chronic hypoxia induced demethylation on genomic DNA and decreased the expression of DNA methyltransferase 3b (DNMT3b) in vivo. We further found that DNMTs inhibition elevated the protein levels of amyloid precursor protein, β- and γ-secretases, whereas overexpression of DNMT3b suppressed the levels of them in vitro. Discussion Our study suggests chronic hypoxia can aggravate AD progression through demethylation of genes encoding γ-secretase components by downregulation of DNMT3b.