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Neuronal ACLY decreased in both AD patients and mice. ACLY knockdown in young 5\u00d7FAD mice exacerbated dystrophic neurites, aggravated A\u03b2 deposition, and obstructed autophagic\u2010lysosomal flux. Conversely, enhancing ACLY improved cognition in advanced 5\u00d7FAD mice. Mechanistically, ACLY regulates lysosomal vacuolar adenosine triphosphatase assembly and acidification through \u03b1\u2010tubulin acetylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Neuronal ACLY maintains microtubule stability and cognition, while critically regulating lysosomal acidification\u2010mediated amyloid pathology. These findings reveal novel mechanisms linking lysosomal dysfunction to AD, offering therapeutic insights.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>ATP citrate lyase (ACLY) as highly expressed in the processes of hippocampal neurons is essential for maintaining learning and memory through tubulin acetylation\u2010mediated microtubule stability.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ACLY deficiency obstructed autophagic\u2013lysosomal flux, aggravated amyloid beta deposition, and exacerbated dystrophic neurites in the early stages of Alzheimer's disease (AD).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Enhanced neuronal ACLY promoted synaptic plasticity and alleviates cognitive impairment in AD mice with advanced neuropathology.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ACLY regulates lysosomal vacuolar adenosine triphosphatase subunit assembly and lysosomal acidification via \u03b1\u2010tubulin acetylation in the AD brain.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70919","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T09:27:53Z","timestamp":1763544473000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ACLY regulates autolysosome acidification through tubulin acetylation\u2010mediated assembly of V\u2010ATPase subunits in Alzheimer's disease model mice"],"prefix":"10.1002","volume":"21","author":[{"given":"Anlan","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Neurology Fujian Medical University Union Hospital Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience Fujian Medical University  Fuzhou China"},{"name":"The School of Basic Medical Sciences Public Technology Service Center Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoman","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Neurology Fujian Medical University Union Hospital Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology Fujian Medical University Union Hospital 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