Methyl-CpG Binding Protein 2 in Alzheimer Dementia

Despite decades of research on Alzheimer disease, understanding the complexity of the genetic and molecular interactions involved in its pathogenesis remains far from our grasp. Methyl-CpG Binding Protein 2 (MeCP2) is an important epigenetic regulator enriched in the brain, and recent findings have implicated MeCP2 as a crucial player in Alzheimer disease. Here, we provide comprehensive insights into the pathophysiological roles of MeCP2 in Alzheimer disease. In particular, we focus on how the alteration of MeCP2 expression can impact Alzheimer disease through risk genes, amyloid-β and tau pathology, cell death and neurodegeneration, and cellular senescence. We suggest that Alzheimer disease can be adversely affected by upregulated MeCP2-dependent repression of risk genes (MEF2C, ADAM10, and PM20D1), increased tau accumulation, and neurodegeneration through neuronal cell death (excitotoxicity and apoptosis). In addition, we propose that the progression of Alzheimer disease could be caused by reduced MeCP2-mediated enhancement of astrocytic and microglial senescence and consequent glial SASP (senescence-associated secretory phenotype)-dependent neuroinflammation. We surmise that any imbalance in MeCP2 function would accelerate or cause Alzheimer disease pathogenesis, implying that MeCP2 may be a potential drug target for the treatment and prevention of Alzheimer disease.