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

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 obstructed autophagic-lysosomal flux. Conversely, enhancing ACLY improved cognition in advanced 5×FAD mice. Mechanistically, ACLY regulates lysosomal vacuolar adenosine triphosphatase assembly and acidification through α-tubulin acetylation. DISCUSSION: Neuronal ACLY maintains microtubule stability and cognition, while critically regulating lysosomal acidification-mediated amyloid pathology. These findings reveal novel mechanisms linking lysosomal dysfunction to AD, offering therapeutic insights. HIGHLIGHTS: ATP citrate lyase (ACLY) as highly expressed in the processes of hippocampal neurons is essential for maintaining learning and memory through tubulin acetylation-mediated microtubule stability. ACLY deficiency obstructed autophagic-lysosomal flux, aggravated amyloid beta deposition, and exacerbated dystrophic neurites in the early stages of Alzheimer's disease (AD). Enhanced neuronal ACLY promoted synaptic plasticity and alleviates cognitive impairment in AD mice with advanced neuropathology. ACLY regulates lysosomal vacuolar adenosine triphosphatase subunit assembly and lysosomal acidification via α-tubulin acetylation in the AD brain.