Dysregulation of amyloid-β metabolism by impaired METTL3-m6A signaling in Alzheimer's Disease

Deposition of amyloid plaques is a major pathological hallmark in brains of Alzheimer’s disease (AD). Excess accumulation of amyloid-β (Aβ), caused by increased Aβ production and impaired Aβ degradation, leads to progressive brain degeneration in AD patients; hence reducing Aβ accumulation should be highly beneficial to

amyloid pathology in AD brain. N6-methyladenosine (m6A) methylation of RNA is the most prevalent, abundant and conserved internal modification in eukaryotic RNAs and it influences fundamental aspects of RNA metabolism including degradation, translation, splicing, and nuclear export. While RNA m6A dysregulation is implicated in the neurodegenerative diseases, the potential role of RNA m6A dysregulation in

Aβ metabolism (production and degradation) in AD has never been investigated. Our group reported that neuronal METTL3-m6A reduction contributes to neurodegeneration in Alzheimer’s Disease (AD). Both methylation profiling and a sequence-based m6A modification site predictor identified multiple m6A sites in the

mRNAs of APP, its secretases and Aβ-degrading enzymes. Our preliminary results demonstrated that METTL3 reduction led to significantly increased Aβ level likely through modulation of Aβ metabolism genes. Based on these studies, we hypothesized that METTL3-mediated m6A reduction modulates gene expressions in Aβ metabolism-related pathways and contributes to the amyloid pathology of AD. We

will determine the effect of METTL3 deficiency-mediated m6A reduction on mRNA metabolisms by affecting the decay, translation, splicing and nuclear export in primary neurons. The successful completion of this study will provide novel mechanistic insights into Aβ accumulation and amyloid pathology in AD. Identifying a

molecular target for Aβ metabolism will offer new venue for therapeutic intervention for AD.