By Helen Luojia Zhang
Alzheimer’s disease (AD) is a neurodegenerative disorder and is the most common cause of dementia. People with Alzheimer’s often suffer from cognitive impairment such as loss of memory, confusion and depression. AD is a complex multifactorial disease affected by both genetic and epigenetic factors. Several genetic alterations related to Alzheimer’s have been identified through genome-wide associated study (Bodily et al., 2016). However, these only make contributions to a small proportion of Alzheimer’s Disease. Recently, more evidence shows that epigenetic mechanisms play a crucial role in the pathogenesis of Alzheimer’s. Epigenetic changes alter gene expression without changing the primary sequence of DNA. Among which, DNA methylation is by far the best-understood epigenetic mechanism of AD.
DNA methylation typically acts on cytosine residues in the cytosine-guanine-rich regions of DNA known as CpG islands. DNA methyltransferases catalyse the process by adding a methyl group onto the C5 atom of cytosine to form 5-methylcytosine (5mC). Studies have indicated that cytosine methylation levels decrease with age in a few different human tissues. (Fuke et al., 2004). Neuronal immunoreactivity of DNA methylation markers in several AD-related genes showed significant decrease in AD patients compared with cognitive normal controls of similar age, indicating potential association between DNA methylation level and Alzheimer’s Disease (Mastroeni et al., 2010). There is also no conclusive relationship between global DNA methylation pattern and Alzheimer’s. Therefore, attention has been shifted to the effect of gene-specific methylation on the risk of AD.
One of the typical characteristics of Alzheimer’s is the accumulation of whitish plaques made up of abnormally folded amyloid-beta protein (Aβ). The expression of several genes related to Aβ, including PS1, BACE and APP genes, are promoted by decreased level of DNA methylation (Qazi et al., 2017). Presenilin1 protein (PS1) and β-site amyloid precursor protein cleaving enzyme (BACE) function to cleave Aβ precursor protein (APP) to form Aβ, which could promote pathogenesis of AD. Hypomethylation of PS1, BACE and APP genes activates their transcription, ultimately leading to higher production of Aβ, and therefore Alzheimer’s (Lin et al., 2009). In addition, higher levels of DNA methylation are associated with a higher presence of APOE ε4 allele, which encodes apolipoprotein4 (APOE4), an isoform that cannot effectively carry out its β-amyloid degradation task (Di Francesco et al., 2015).
Neurofibrillary tangles (NFTs) formed by aggregates of hyperphosphorylated tau protein, is another pathological hallmark of AD. The equilibrium of tau phosphorylation is mainly regulated by glycogen synthase kinase 3β (GSK3β) and Protein phosphatase 2A (PP2A). A decreased methylation level of GSK3β promoter results in overexpression of GSK3β, which phosphorylates more tau proteins (Nicolia et al., 2010). In contrast, hypomethylation results in reduced activity of PP2A, and thus cannot function properly to dephosphorylate tau, leading to hyperphosphorylated tau protein.
Many abnormal epigenetic regulations are associated with Alzheimer’s Disease, so epigenetic therapy targeted on specific genes may serve as potential treatment for AD. A large number of genes are hypomethylated in AD, thus special diets with methyl donor such as folic acid, S-adenosylmethionine (SAM) and vitamin B12 can repress the progression of Alzheimer’s (Durga et al., 2007). Likewise, DNA demethylating agent such as 5-azadeoxycytidine are crucial to treat hypermethylated genes in AD (Singh et al., 2009). Inhibiting the causing agents involved in modifying DNA methylation pattern may also serve as a potential approach to treating AD. In addition, aberrations in DNA methylation pattern could also be used as a biomarker to predict the risk of AD, allowing its early detection and treatment.
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