The role of m6A modification in the risk prediction and Notch1 pathway of Alzheimer's disease.

ABSTRACT

N6-methyladenosine (m6A) methylation and abnormal immune responses are implicated in neurodegenerative diseases, yet their relationship in Alzheimer's disease (AD) remains unclear. We obtained AD datasets from GEO databases and used AD mouse and cell models, observing abnormal expression of m6A genes in the AD group, alongside disruptions in the immune microenvironment. Key m6A genes (YTHDF2, LRPPRC, and FTO) selected by machine learning were associated with the Notch pathway, with FTO and Notch1 displaying the strongest correlation. Specifically, FTO expression decreased and m6A methylation of Notch1 increased in AD mouse and cell models. We further silenced FTO expression in HT22 cells, resulting in upregulation of the Notch1 signaling pathway. Additionally, increased Notch1 expression in dendritic cells heightened inflammatory cytokine secretion in vitro. These results suggest that reduced FTO expression may contribute to the pathogenesis of AD by activating the Notch1 pathway to interfere with the immune response.