STAT3 mediated the isoleucine-induced Alzheimer's disease progression.
Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts millions globally, with rising prevalence among the aging population, emphasizing the need for effective interventions. Isoleucine, a branched-chain amino acid, crosses the blood-brain barrier and plays a role in various neurological disorders. In this study, we investigated the association of isoleucine with AD traits using the BXD mouse reference population, revealing significant correlations with Y-maze performance, anxiety assays, contextual fear conditioning, and the age of onset for working memory deficits. In vitro, exogenous isoleucine supplementation in HT22 and PC12 cells increased amyloid precursor protein (APP) and phosphorylated tau (p-tau) levels. Subsequent analysis identified 2,000 probes correlated with isoleucine and revealed STAT3 as a candidate downstream regulator. Overexpression of STAT3 increased APP and p-tau levels, and STAT3 inhibition abolished this effect, suggesting that isoleucine modulates AD progression via STAT3 activation. Mendelian randomization analysis further supported a causal relationship between elevated isoleucine levels and AD risk. This work provides insights into isoleucine as a potential risk factor for AD and identifies STAT3 as a mediator of isoleucine-related AD susceptibility.