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bioRxiv · 10.1101/2025.11.03.686106

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

Noorani, A. A.·Islam, S.·Catalfano, K.·Wilkins, H. M.·Blagg, B. S. J.·Zou, K.·Wolfe, M. S.
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Abstract

Deposition of amyloid {beta}-protein (A{beta}) is a hallmark of Alzheimers disease (AD), produced by {gamma}-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 A{beta} production remain unclear. Here, we show that knockdown of endogenous AHA1 decreases A{beta} generation and reduces APP and {gamma}-secretase components, whereas AHA1 overexpression elevates A{beta} production and the expression of these proteins. The AHA1-E67K mutant, which has impaired Hsp90 binding, lowers A{beta} production and the levels of APP and {gamma}-secretase components compared with wild-type AHA1. AHA1 associates with APP and immature {gamma}-secretase components, including anterior pharynx-defective phenotype 1 (APH1), indicating its role in APP proteolysis and A{beta} production. Disruption of the AHA1/Hsp90 complex--through AHA1 knockdown, the E67K mutant, or a small-molecule inhibitor--reduces {gamma}-secretase assembly. Familial AD mutations in APP-C99 and presenilin-1 (PS1) increase AHA1, Hsp90, APP, and APH1 expression, enhancing A{beta} production. Importantly, AHA1 knockdown decreases abnormal A{beta} generation and C99, PS1-CTF, and APH1 levels in mutant APP cells, while AHA1 overexpression enhances A{beta} production in PS1 mutant cells. Collectively, these findings reveal that AHA1 regulates A{beta} production by modulating APP expression and {gamma}-secretase assembly, establishing AHA1 as a potential target for therapeutic intervention in AD.

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Noorani, A. A., Islam, S., Catalfano, K., Wilkins, H. M., Blagg, B. S. J., Zou, K., Wolfe, M. S.. 2025-11-04. AHA1 regulates Aβ production via modulation of APP expression and γ-secretase assembly. https://doi.org/10.1101/2025.11.03.686106

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