ACLY regulates autolysosome acidification through tubulin acetylation-mediated assembly of V-ATPase subunits in Alzheimer's disease model mice.

ABSTRACT:

Introduction

Faulty autolysosome acidification leads to dystrophic neurites-an early event propelling Alzheimer's disease (AD) progression-yet the underlying mechanism remains elusive.

Methods

To elucidate the physiological functions of neuronal ATP citrate lyase (ACLY) expression, its impact on amyloid beta (Aβ) pathology, and molecular mechanisms, we used intracerebroventricular ACLY inhibitor administration, adeno-associated virus-mediated ACLY modulation in the dorsal hippocampus, and N2a-swAPP695 cell line.

Results

Inhibition or knockdown ACLY reduced microtubule stability and impaired cognition in wild-type mice. Neuronal ACLY decreased in both AD patients and mice. ACLY knockdown in young 5×FAD mice exacerbated dystrophic neurites, aggravated Aβ deposition, and

SUBMITTER: Lin A 

PROVIDER: S-EPMC12627967 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature