Cftr nominates a novel therapeutic target for Alzheimer's disease: Evidence from integrative omics and in vitro validation

Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3 × Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including C5ar1, Gabrg1, Ptger1, Tac1, LPAR2, Pnp2, CFTR, and SSTR3. PCR-based validation in both in vivo and in vitro models confirmed CFTR as the most promising candidate for further investigation. In Aβ₂₅-₃₅-induced cellular AD models, CFTR knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing CFTR activity attenuated these pathological processes. These results establish CFTR as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.

Alzheimer's disease; Cftr; Metabolomics; NLRP3 inflammasome; Neuroinflammation; Transcriptomics.