Research Progress of Epigenetic Modification in The Regulation of Alzheimer's Disease

Alzheimer's disease (AD) is a clinically common neurodegenerative disease characterized by progressive cognitive dysfunction and memory loss. In recent years, studies have found that various epigenetic modifications such as DNA modification, histone modification, RNA modification and non-coding RNA play pivotal roles in the regulation of A beta deposition, hyperphosphorylated Tau proteins, nerve regeneration, synaptic plasticity and cognitive function, thereby improving or aggravating the pathological process of AD. Decreasing 5-methylcytosine of PSEN1 and BACE1 genes may cause A beta production via promotion of PSEN1 and BACE1 expression. Increasing DNA modifications of 5-hydroxymethylcytosine by Tet1/Tet2/Tet3 protein can regulate proliferation, differentiation and function of neurons, neural stem cells, and neural progenitor cells. Moreover, increasing histone methylation (H3K9me2 and H3K4me3) and demethylation (H3K27me3) catalyzed by histone methyltransferase and demethylase respectively can decrease neuronal differentiation and cognition. Low acetylation levels of histones maintained by the suppression of histone acetylases and activation of histone deacetylases (HDAC2, HDAC3 and HDAC6) can be contributed to inducing cognitive impairment. Furthermore, N-6-methyladenosine (m6A) RNA modification catalyzed by the RNA methyltransferases Mettl3 and Mettl14 (writers), removed by the demethylases FTO (erasers), and interacted with m6A-binding proteins YTHDF1 and YTHDF (readers) is involved in synaptic plasticity, neuronal apoptosis and synaptic transmission. In addition, low expression of miR-29, miR-31 and miR-101 causes A beta deposition by improving BACE1 and APP levels. Either declining miR-34a, miR-219 or raising miR-128a, miR-125b, and miR-124 can lead to high levels of Tau protein and Tau hyperphosphorylation. The up-regulation of miR-137 and miR-142 can reduce synaptic plasticity and stimulate neuroinflammation, respectively. Overexpression of lncRNA BACE1-AS and BC200 can promote A beta deposition by boosting BACE1 expression, while enhancing BDNF-AS and GDNFOS result in neurodevelopment disorder by inhibiting BDNF and GDNF expression. Clinical data shows that changes in epigenetic modifications are significantly correlated with AD risk. The use of drugs, physical stimulation, siRNA and other interventions to change the level of epigenetic modifications in AD animal models can ameliorate AD pathology and cognitive impairment. Our paper reviews the regulatory effects of various epigenetic modifications in AD and in the hope of providing a theoretical basis for further understanding of the epigenetic mechanism in AD and a feasible interventions for preventing or treating AD via alteration epigenetic modifications.