Integrated transcriptomic and proteomic analysis identifies FBXW7 as a key regulator of tau homeostasis in Alzheimer's disease

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by complex, incompletely understood genetic and pathogenic factors. E3 ubiquitin ligases (E3s), crucial for protein degradation, are implicated in AD, but their specific contributions to its progression remain to be elucidated. Objective This study aimed to identify dysregulated E3s in AD and elucidate the role of a hub E3, FBXW7, in its pathogenesis and tau protein regulation. Methods We integrated four datasets to identify differentially expressed E3s (DE-E3s) in AD and performed functional enrichment and PPI network analyses. Machine learning identified hub E3s and stratified AD patients into molecular subtypes. Furthermore, we validated the expression and functional role of FBXW7 using western blot, immunoprecipitation-mass spectrometry (IP-MS), and co-immunoprecipitation (Co-IP). Results We identified 42 DE-E3s primarily enriched in protein ubiquitination and Notch signaling pathways. FBXW7 and ENC1 emerged as hub E3s, stratifying patients into two subtypes. Subtype I exhibited enrichment of inflammatory pathways, suggesting immune dysregulation. Conversely, subtype II displayed activation of pathways associated with synaptic dysfunction and neuronal loss, potentially representing distinct primary pathological features. Furthermore, we observed decreased FBXW7 expression in AD models compared to controls. Notably, FBXW7 interacted with Tau protein. Overexpression of FBXW7 reduced the levels of both total Tau and p-Tau Ser262, and this reduction in Tau levels was reversed by MG132 treatment. Conclusions This study comprehensively identified E3s associated with AD, with our findings highlighting FBXW7 as a potential key regulator of AD pathogenesis through its modulation of tau protein levels.