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The disruption of neuronal histone acetylation homeostasis mediated by Tip60 HAT is a common early event in neurodegenerative diseases, but the deeper regulatory mechanism on \u03b2\u2010amyloid peptide (A\u03b2)\u2010induced neurotoxicity and autophagic function in AD is still unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>AD models were established both in APP\/PS1 mice and A\u03b2<jats:sub>1\u201342<\/jats:sub>\u2010treated SH\u2010SY5Y cells. The Morris water maze test (MWM) was performed to examine mouse cognitive function. Neurological damage in the hippocampus was observed by hematoxylin\u2013eosin (H&amp;E), Nissl's, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and NeuN staining. Autophagosome\u2010lysosome fusion was detected by immunohistochemistry, immunofluorescence, and Lyso\u2010Tracker Red staining. Cell viability and apoptosis were evaluated by CCK\u20108 assay and flow cytometry. The molecular interactions were verified by co\u2010immunoprecipitation (Co\u2010IP), dual luciferase assays, and ChIP detections. The RNA and autophagy\u2010lysosome\u2010related proteins were assessed by Western blot and RT\u2010qPCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TIP60 overexpression improved cognitive deficits and neurological damage and restored the impairment of autophagy\u2010lysosomes fusion in\u00a0vivo. Similarly, the upregulation of TIP60 in A\u03b2<jats:sub>1\u201342<\/jats:sub>\u2010treated SH\u2010SY5Y cells suppressed neuronal apoptosis and tau phosphorylation through the activating autophagy\u2010lysosome pathway. Mechanistically, TIP60 activated IKK\u03b2 transcription by promoting SOX4 acetylation, thus leading to the translocation of SNAP23 to STX17\u2010contained autophagosomes. Moreover, the protective roles of TIP60 in neuron damage were abolished by the inhibition of SOX4\/IKK\u03b2 signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Collectively, our results highlighted the potential of the TIP60 target for AD and provided new insights into the mechanisms underlying neuroprotection in this disorder.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70095","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T02:41:12Z","timestamp":1730860872000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Lysine Acetyltransferase TIP60 Restricts Nerve Injury by Activating IKK\u03b2\/SNAP23 Axis\u2010Mediated Autophagosome\u2010Lysosome Fusion in Alzheimer's Disease"],"prefix":"10.1111","volume":"30","author":[{"given":"Wei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology, The 2nd Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang Jiangxi Province P.R. 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