{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:07:40Z","timestamp":1789564060001,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,10]]},"group-title":"Neuroscience","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01AG054517"],"award-info":[{"award-number":["R01AG054517"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG063743"],"award-info":[{"award-number":["R01AG063743"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The complement system, a proteolytic cascade crucial for innate immune system function, is dysregulated in brain aging and neurodegenerative diseases, including Alzheimer Disease (AD). In models of AD, complement proteins, including C1q and C3, are upregulated and mediate microglial clearance of amyloid plaques and pruning of synapses. Among complement genes,\n                  <jats:italic>C4b<\/jats:italic>\n                  , which in mice encodes complement protein C4, is the most highly upregulated in astrocytes in the setting of aging and amyloid pathology. While C4 plays a key role in the complement cascade, there have been no investigations of the direct role of C4 in regulating AD pathology. To probe the function of C4 in amyloid plaque-related pathology, we crossed a germ line\n                  <jats:italic>C4b<\/jats:italic>\n                  knockout mouse (C4 KO) to the 5XFAD mouse model of AD-related amyloidosis. To our surprise, we observed striking reductions in amyloid plaque pathology across multiple brain regions in 5XFAD-C4 KO mice relative to standard 5XFAD controls. This reduction in plaque burden stands in sharp contrast to previous reports of C3 deletion in AD models, which increases plaques. Additionally, we observed a reduction in neuroinflammation and peri-plaque glial clustering in 5XFAD-C4 KO mice, suggestive of a role for C4 in regulating overall neuroinflammatory tone in AD. Finally, we observed a phenotypic shift of the peri-plaque microglia to a more reactive disease-associated microglia (DAM) phenotype, indicating that C4 could be an important factor in regulating microglial reactivity in AD. Altogether, our results demonstrate that C4 may have functions beyond the classical complement cascade and may serve as a key facilitator of AD-related glial function and pathology and a possible target for therapeutic modification.\n                <\/jats:p>","DOI":"10.64898\/2026.09.09.750237","type":"posted-content","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:25:39Z","timestamp":1789136739000},"source":"Crossref","is-referenced-by-count":0,"title":["Complement component C4 regulates amyloid pathology and glial reactivity in mouse model of Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"given":"Collin J.","family":"Nadarajah","sequence":"first","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle Y.","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohui","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer H.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma P.","family":"Danhash","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste M.","family":"Karch","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-0360","authenticated-orcid":false,"given":"Erik S.","family":"Musiek","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"Center On Biological Rhythms And Sleep and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091605350977000_2026.09.09.750237v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.09.001"},{"key":"2026091605350977000_2026.09.09.750237v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00391-w"},{"key":"2026091605350977000_2026.09.09.750237v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)70016-5"},{"key":"2026091605350977000_2026.09.09.750237v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0624-8"},{"key":"2026091605350977000_2026.09.09.750237v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01791-4"},{"key":"2026091605350977000_2026.09.09.750237v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.018"},{"key":"2026091605350977000_2026.09.09.750237v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.08.008"},{"key":"2026091605350977000_2026.09.09.750237v1.8","unstructured":"Charles A Janeway, J. , Travers, P. , Walport, M. & Shlomchik, M. 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