Integrated multi-omics analysis identifies potential therapeutic targets for Alzheimer’s disease

Abstract Because the pathogenesis of Alzheimer’s disease is multifactorial and complex, integrated multi-level omics analysis is essential to comprehensively elucidate its molecular alterations. We therefore utilized the well-established amyloid precursor protein/presenilin 1 mouse model to carry out an integrated multi-omics study using transcriptomic, proteomic, N 6 -methyladenosine epitranscriptomic, and phosphoproteomic analyses. The results revealed substantial molecular alterations across multiple biological dimensions and the alteration in the expression of several key genes, such as GFAP , APP , and RTN4 , in a mouse model of Alzheimer’s disease. The pronounced elevation of RTN4 in reactive astrocytes is indicative of its involvement in Alzheimer’s disease pathogenesis. Furthermore, we identified dysregulation of pathways related to endocytosis, highlighting the critical role of this process in disease progression. Our findings underscore the significant impact of post-transcriptional (N 6 -methyladenosine methylation) and post-translational (phosphorylation) protein modifications, which have been underrepresented in Alzheimer’s disease research. The significant contribution made by this study is the integrated, multi-level omics analysis that we carried out to investigate the complex biological changes that occur in Alzheimer’s disease. Our findings provide novel insights into Alzheimer’s disease pathogenesis and suggest potential therapeutic targets, such as RTN4.