{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:25:39Z","timestamp":1786119939501,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,4]]},"group-title":"Neuroscience","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Biological sex is a major determinant of Alzheimer\u2019s disease prevalence, yet the molecular mechanisms underlying sex-specific vulnerability remain largely unknown. Metabotropic glutamate receptor 5 (mGluR5) functions as a co-receptor for \u03b2-amyloid (A\u03b242) oligomer\/cellular prion protein (PrP\n                  <jats:sup>C<\/jats:sup>\n                  )-mediated pathogenic signaling in males but not females, establishing a sex-dimorphic node in \u03b2-amyloid pathophysiology whose regulatory basis is undefined. Using quantitative proteomic analysis, we identify the E3 ubiquitin ligase TRIM9 as a novel mGluR5-interacting protein and a previously unrecognized sex-specific regulator of the A\u03b242\/PrP\n                  <jats:sup>C<\/jats:sup>\n                  \/mGluR5 complex. TRIM9 selectively associates with mGluR5 in male but not female APP\/PS1 mouse brain and is required for mGluR5 to serve as a co-receptor for PrP\n                  <jats:sup>C<\/jats:sup>\n                  -dependent A\u03b242 oligomer binding. Genetic deletion of TRIM9 abolishes A\u03b242\/PrP\n                  <jats:sup>C<\/jats:sup>\n                  \/mGluR5 complex assembly in male APP\/PS1 mice demonstrating that TRIM9 is an essential scaffold for male-specific A\u03b242 signal transduction. Loss of TRIM9 in males further reduces \u03b2-amyloid pathology by restoring Akt\/GSK3\u03b2\/ZBTB16-dependent autophagic flux, linking disruption of this complex to a defined downstream proteostatic mechanism. Together, these findings establish TRIM9 as a critical molecular determinant coupling male-specific A\u03b242\/PrP\n                  <jats:sup>C<\/jats:sup>\n                  \/mGluR5 complex assembly to downstream neurodegenerative signaling and \u03b2-amyloid pathology. They reveal an unappreciated layer of sex-dependent complexity in mGluR5 pharmacology and identify disruption of the TRIM9\/mGluR5 interaction as a potential male-specific therapeutic strategy for Alzheimer\u2019s disease.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    The molecular basis of sex differences in Alzheimer\u2019s disease vulnerability remains unresolved. We show that mGluR5 functions as a male-specific co-receptor for pathogenic A\u03b242\/PrP\n                    <jats:sup>C<\/jats:sup>\n                    signaling and identify the E3 ubiquitin ligase TRIM9 as the factor governing this dimorphism. TRIM9 selectively assembles the A\u03b242\/PrP\n                    <jats:sup>C<\/jats:sup>\n                    \/mGluR5 complex in male brain, and its genetic deletion disrupts complex formation while restoring Akt\/GSK3\u03b2-dependent autophagic clearance of amyloid. These findings define a sex-specific signaling axis underlying \u03b2-amyloid pathogenesis and establish TRIM9 as a candidate target for sex-informed Alzheimer\u2019s therapeutics.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.30.741783","type":"posted-content","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:30:17Z","timestamp":1785850217000},"source":"Crossref","is-referenced-by-count":0,"title":["TRIM9 Determines Sex-Specific \u03b2-Amyloid\/Cellular Prion Protein\/mGluR5 Complex Formation and Pathological Signaling in Alzheimer\u2019s Disease Mice"],"prefix":"10.64898","author":[{"given":"Fatemeh","family":"Babaei","sequence":"first","affiliation":[{"name":"University of Ottawa Brain and Mind Institute"},{"name":"Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh A.","family":"Panahi","sequence":"additional","affiliation":[{"name":"University of Ottawa Brain and Mind Institute"},{"name":"Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tash-Lynn L.","family":"Colson","sequence":"additional","affiliation":[{"name":"University of Ottawa Brain and Mind Institute"},{"name":"Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Cheng","sequence":"additional","affiliation":[{"name":"University of Ottawa Brain and Mind Institute"},{"name":"Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Tiberi","sequence":"additional","affiliation":[{"name":"University of Ottawa Brain and Mind Institute"},{"name":"Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada"},{"name":"Department of Psychiatry. University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada"},{"name":"Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rony","family":"Chidiac","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pharmacologie-Physiologie, Universit\u00e9 de Sherbrooke - Campus de la Sant\u00e9, 3001, 12e Avenue Nord, Sherbrooke, Quebec, J1H 5N4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7241-9044","authenticated-orcid":false,"given":"Stephane","family":"Anger","sequence":"additional","affiliation":[{"name":"Donnelly Centre for Cellular and Biomolecular Research, Temerty Faculty of Medicine, University of Toronto, 160 College St, Rm 808, Toronto, Ontario, M58 3E1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0087-5432","authenticated-orcid":false,"given":"Stephanie L.","family":"Gupton","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"},{"name":"Department of UNC Neuroscience Center University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"},{"name":"Department of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled S.","family":"Abd-Elrahman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Pharmacology and Therapeutics, and Djavad Monaghan Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt"},{"name":"Department of Medical Sciences, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi 127788, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen S. 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