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This study investigated the role of CLU in regulating microglial inflammation, amyloid pathology, and cognitive function in CLU-deficient and AD models. CLU synthesis and secretion in microglia were highly dynamic, with minimal expression at rest but markedly increased expression upon pro-inflammatory stimulation. CLU deficiency amplified microglial activation and inflammatory responses, whereas introducing recombinant CLU protein reduced microglial inflammation. In a human mutant APP knock-in AD mouse model, loss of CLU impaired learning and memory despite a reduced amyloid burden. snRNA-seq analysis further revealed that CLU loss disrupted the balance between excitatory and inhibitory neurons. These findings provide novel insights indicating that CLU likely functions as a negative feedback regulator of microglial activation and inflammation, thereby promoting microglial resolution and neuronal homeostasis, and consequently, cognitive outcomes independent of amyloid pathology.<\/jats:p>","DOI":"10.64898\/2026.07.30.741791","type":"posted-content","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T06:00:15Z","timestamp":1785909615000},"source":"Crossref","is-referenced-by-count":0,"title":["Clusterin regulates microglial inflammation and cognitive function independent of amyloid pathology in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Punam","family":"Rawal","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee-Jung","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Khatri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"Larson","sequence":"additional","affiliation":[{"name":"Transgenic and Gene Targeting Institutional Facility, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay L.","family":"Vivian","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetics, Department of Pediatrics, Children\u2019s Mercy Hospital, Kansas City, MO, USA"},{"name":"University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA"},{"name":"Neuroscience Graduate Program, University of Kansas, Lawrence, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080604300740000_2026.07.30.741791v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.440"},{"key":"2026080604300740000_2026.07.30.741791v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2802"},{"key":"2026080604300740000_2026.07.30.741791v1.3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrneurol.2009.213","article-title":"New light on an old CLU","volume":"6","year":"2010","journal-title":"Nature Reviews Neurology"},{"key":"2026080604300740000_2026.07.30.741791v1.4","doi-asserted-by":"crossref","first-page":"164","DOI":"10.3389\/fnins.2019.00164","article-title":"Clusterin in Alzheimer\u2019s disease: mechanisms, genetics, and lessons from other pathologies","volume":"13","year":"2019","journal-title":"Frontiers in neuroscience"},{"key":"2026080604300740000_2026.07.30.741791v1.5","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1998.6892"},{"key":"2026080604300740000_2026.07.30.741791v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s004010050815"},{"key":"2026080604300740000_2026.07.30.741791v1.7","doi-asserted-by":"publisher","DOI":"10.1042\/bj2930027"},{"key":"2026080604300740000_2026.07.30.741791v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-008-9588-x"},{"key":"2026080604300740000_2026.07.30.741791v1.9","doi-asserted-by":"publisher","DOI":"10.1001\/archgenpsychiatry.2010.78"},{"key":"2026080604300740000_2026.07.30.741791v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2011.07.056"},{"key":"2026080604300740000_2026.07.30.741791v1.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028527"},{"key":"2026080604300740000_2026.07.30.741791v1.12","doi-asserted-by":"crossref","unstructured":"S. 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