Fig. 5
From: Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease
Physiological and pathological impact of global methylation and therapeutic approaches. Tau protein mapped for methylation in physiological and pathological state has shown reduced methylation in pathological conditions. During Alzheimer disease, the overall methylation potential of neurons get reduced, which affects Tau function as well as regulation at epigenetic level. There are 14 methylation sites in normal state, out of which 8 sites can be dimethylated (shown in blue) while only 7 Tau methylation sites are found in Alzheimer disease. On epigenetic level, differential methylation signatures on histones as well as DNA leads to increase in phosphorylated Tau burden, Tau aggregation and amyloid-β deposition. However, methylation is highly regulated modification and functions both in gene silencing and activation. Thus, methylation as an epigenetic regulator can be both protective and deleterious in case of AD. Therapeutic strategies employing the specific DNMT inhibitors and modulators of histone and DNA methylation may prove to be useful against AD. On the other hand, aberrant Tau and/or DNA/histone methylation involves deregulation of one carbon metabolism lowering the SAM: SAH ratio. Strategies to replenish SAM: SAH ratio can aid to protect neurons against oxidative stress, aggregate burden and deleterious effects of Tau and DNA hypomethylation