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With no effective cure available, research continues to explore novel therapeutic and preventive strategies. Recently, palmitic acid\u2010hydroxystearic acids (PAHSAs), especially their stereochemistry S\u2010configuration, have shown potential as a dietary supplement with anti\u2010inflammatory and anti\u2010diabetic properties. We previously found that one of the PAHSAs, 9\u2010PAHSA, could improve cognitive impairment in the high\u2010fat\u2010diet mice, however, whether it has an equal effect on\n                    <jats:sc>AD<\/jats:sc>\n                    \u2010like mice remains unclear. Since mitochondrial dysfunction is recognized as a significant pathological feature of\n                    <jats:sc>AD<\/jats:sc>\n                    , with impaired mitophagy leading to the accumulation of dysfunctional mitochondria, thus exacerbating disease progression, in this study, we evaluated the effects of the chiral isomer of 9\u2010PAHSA, S\u20109\u2010PAHSA, on cognitive dysfunction and mitochondrial dysfunction in 5xFAD mice. Three\u2010month\u2010old mice were treated with S\u20109\u2010PAHSA 30\u2009mg\/kg in their drinking water for 3\u2009months. Behavioral studies were conducted using the Morris Water Maze (MWM) and Y\u2010maze tests, followed by assessments of amyloid\u2010beta (A\u03b2) plaque deposition, neuronal apoptosis, and mitochondrial function. We found that S\u20109\u2010PAHSA significantly enhanced spatial learning and memory abilities, reduced amyloid plaque deposition, decreased neuronal apoptosis, and improved mitochondrial homeostasis and autophagy in 5xFAD mice. These findings suggest that S\u20109\u2010PAHSA holds promise as a supplementary preventive and therapeutic strategy for\n                    <jats:sc>AD<\/jats:sc>\n                    treatment.\n                  <\/jats:p>","DOI":"10.1111\/ejn.70118","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T03:45:24Z","timestamp":1745552724000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["S\u20109\u2010PAHSA Attenuates A\u03b2 Accumulation and Improves Cognitive Deficits by Promoting Mitochondrial Autophagy in 5xFAD Mice"],"prefix":"10.1111","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2096-1241","authenticated-orcid":false,"given":"Chenyu","family":"Lu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Translational Neuroscience, 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