Astrocytic Mettl14 depletion enhances cognitive function by attenuating astrogliosis via the DUSP1/MAPK pathway in APP/PS1 mice: targeting neuroinflammation in Alzheimer's disease.

Abstract

Alzheimer's disease (AD), a leading cause of dementia, represents a critical unmet global medical need. While the precise mechanisms underlying AD pathogenesis remain elusive, increasing evidence underscores the pivotal role of neuroinflammation in driving cognitive impairment. N6-methyladenosine (m6A), an epigenetic modification regulating RNA metabolism, has been found to be dysregulated in AD. In this study, we used a Mettl14 conditional knockout APP/PS1 mouse model (AD-cKO mice) to investigate the effects of modulating astrocytic m6A levels on AD progression. Our comprehensive histological, biochemical, and transcriptomic analyses revealed that AD-cKO mice exhibited enhanced cognitive function, along with decreased astrogliosis and reduced neuroinflammation when compared to APP/PS1 control mice. Based on the conjoint analysis of MeRIP-seq and RNA-seq data, our mechanistic studies further demonstrated that the loss of Mettl14 in astrocytes significantly affected the expression of DUSP1, a negative regulator of inflammation, to mitigate MAPK signaling. These findings suggest that targeting m6A regulators, such as Mettl14, may represent a promising therapeutic strategy to control neuroinflammation in AD progression. This study also highlights the broader potential of epigenetic modulation as a novel approach for treating AD. This graphic abstract illustrates the impact of Mettl14-mediated m6A modification on Alzheimer's disease (AD) pathogenesis. Alzheimer's disease, a leading cause of dementia, involves significant neuroinflammation. The study utilizes a Mettl14 conditional knockout APP/PS1 mouse model (AD-cKO mice) to investigate the role of m6A modification in astrocytes, the findings suggest that targeting m6A regulators like Mettl14 offers potential therapeutic benefits for controlling neuroinflammation in AD.