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The complement system has emerged as a central mediator linking acute injury to progressive neuroinflammatory pathology. Following TBI, complement is rapidly activated through classical, lectin, and alternative pathways, converging at C3 and generating downstream effector molecules, including opsonins, anaphylatoxins, and the membrane\u2010attack complex. These mediators amplify inflammation, promote cytotoxic signaling, and exacerbate acute neuronal injury while sustaining chronic microglial and astrocytic activation. In the subacute and chronic phases, complement\u2010dependent opsonization drives maladaptive synaptic pruning, leading to progressive loss of synaptic density and cognitive impairment. Complement activation also contributes to circuit dysfunction and impairs endogenous repair processes by suppressing neurogenesis and neuroblast migration. Preclinical studies consistently identify upstream complement activation, particularly at the level of C3, as a key driver of chronic pathological processes. Consistent with this concept, targeted complement inhibition preserves synaptic integrity and improves functional outcomes. These findings position complement as a promising therapeutic target and support a paradigm shift toward targeting chronic neuroinflammation to prevent long\u2010term neurological sequelae after TBI.<\/jats:p>","DOI":"10.1002\/eji.70230","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T12:37:17Z","timestamp":1781872637000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Complement in Traumatic Brain Injury: Linking Acute Injury to Chronic Neurodegeneration"],"prefix":"10.1002","volume":"56","author":[{"given":"Ariana","family":"Chacon","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy Raheb","family":"Khelo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layth J.M.","family":"Saada","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Grossberg","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Reisner","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Emory University  Atlanta Georgia USA"},{"name":"Neurosurgery, Children's Healthcare of Atlanta  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali M.","family":"Alawieh","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Immunology Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Ralph H. 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