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TREM2 multimers have been identified in crystallography and implicated in the efficacy of antibody therapeutics; however, the molecular basis for TREM2 multimerization remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We used molecular dynamics simulations and binding energy analysis to determine the effects of AD\u2010associated variants on TREM2 multimerization and validated with experimental results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>TREM2 trimers remained stably bound, driven primarily by salt bridge between residues D87 and R76 at the interface of TREM2 units. This salt bridge was disrupted by the AD\u2010associated variants R47H and R98W and nearly ablated by the D87N variant. This decreased binding among TREM2 multimers was validated with co\u2010immunoprecipitation assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>This study uncovers a molecular basis for TREM2 forming stable trimers and unveils a novel mechanism by which TREM2 variants may increase AD risk by disrupting TREM2 oligomerization to impair TREM2 normal function.<\/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>Triggering receptor expressed on myeloid cells 2 (TREM2) multimerization could regulate TREM2 activation and function.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>D87\u2013R76 salt bridges at the interface of TREM2 units drive the formation of stable TREM2 dimers and trimers.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Alzheimer's disease (AD)\u2013associated R47H and R98W variants disrupt the D87\u2013R76 salt bridge.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The AD\u2010associated D87N variant leads to complete loss of the D87\u2013R76 salt bridge.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14124","type":"journal-article","created":{"date-parts":[[2024,7,20]],"date-time":"2024-07-20T07:04:43Z","timestamp":1721459083000},"page":"6332-6350","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Multimerization of TREM2 is impaired by Alzheimer's disease\u2013associated variants"],"prefix":"10.1002","volume":"20","author":[{"given":"Hunter B.","family":"Dean","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering School of Engineering University of Alabama at Birmingham Birmingham Alabama USA"},{"name":"Alzheimer's Disease Center Center for Neurodegeneration and Experimental Therapeutics &amp; Departments of Neurology and Neurobiology Marnix E. Heersink School of Medicine University of Alabama at Birmingham  Birmingham Alabama USA"},{"name":"Medical Scientist Training Program, Marnix E. Heersink School of Medicine University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory A.","family":"Greer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering School of Engineering University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan\u2010Zhong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering School of Engineering University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Elston","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease Center Center for Neurodegeneration and Experimental Therapeutics &amp; Departments of Neurology and Neurobiology Marnix E. 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