Homeostatic DNMT3a Activity Is Required to Restore Cognition and Hippocampal DNA Methylation in the 5xFAD Model of Alzheimer's Disease.

Dysregulation of DNA methylation has been implicated in Alzheimer's disease (AD), making the manipulation of DNA methylation processes a promising therapeutic strategy. DNA methyltransferase 3a (DNMT3a), one of the two de novo DNMTs, is involved in learning and memory. However, it remains elusive whether and how alterations in DNMT3a expression contributes to AD pathogenesis. In this study, we investigated the consequences of DNA methylation dysregulations in the hippocampus of 5xFAD mouse model of AD and explored the use of L-methionine (MET) supplement to restore DNA methylation dysregulations. The 5xFAD model exhibited spatial memory impairments accompanied by global DNA hypomethylation and dysregulated hippocampal expression of DNA methyltransferases (DNMT) and demethylases. Prolonged treatment with MET rescued memory deficits, reduced amyloid-β load, decreased neuroinflammation, restored the expression of plasticity-regulating genes and proteins, and enhanced serotonergic neurotransmission. DNMT3a knockdown diminished the pro-cognitive effects of MET and independently impaired spatial memory and hippocampal neuroplasticity in both wildtype and 5xFAD mice. Interestingly, DNMT3a overexpression also had detrimental effects on spatial memory and hippocampal neuroplasticity in both genotypes. Our findings demonstrate that methyl supplementation can be a promising therapeutic strategy for AD patients with brain DNA hypomethylation and that maintaining DNMT3a homeostasis is crucial for normal cognitive functions and the pro-cognitive effects of MET.