AHA1 regulates Aβ production via modulation of APP expression and γ-secretase assembly

Deposition of amyloid β-protein (Aβ) is a hallmark of Alzheimer’s disease (AD), produced by γ-secretase–mediated cleavage of amyloid precursor protein (APP). The 90-kDa heat shock protein (Hsp90) co-chaperone, activator of Hsp90 ATPase homolog 1 (AHA1), is known to promote the accumulation of toxic tau species; however, its effects on Aβ production remain unclear. Here, we show that knockdown of endogenous AHA1 decreases Aβ generation and reduces APP and γ-secretase components, whereas AHA1 overexpression elevates Aβ production and the expression of these proteins. The AHA1-E67K mutant, which has impaired Hsp90 binding, lowers Aβ production and the levels of APP and γ-secretase components compared with wild-type AHA1. AHA1 associates with APP and immature γ-secretase components, including anterior pharynx-defective phenotype 1 (APH1), indicating its role in APP proteolysis and Aβ production. Disruption of the AHA1/Hsp90 complex—through AHA1 knockdown, the E67K mutant, or a small-molecule inhibitor—reduces γ-secretase assembly. Familial AD mutations in APP-C99 and presenilin-1 (PS1) increase AHA1, Hsp90, APP, and APH1 expression, enhancing Aβ production. Importantly, AHA1 knockdown decreases abnormal Aβ generation and C99, PS1-CTF, and APH1 levels in mutant APP cells, while AHA1 overexpression enhances Aβ production in PS1 mutant cells. Collectively, these findings reveal that AHA1 regulates Aβ production by modulating APP expression and γ-secretase assembly, establishing AHA1 as a potential target for therapeutic intervention in AD.