Complement activation links acute traumatic brain injury to chronic neuroinflammation, maladaptive synaptic pruning, and progressive cognitive decline. These findings support targeted complement inhibition, particularly at the level of C3, as a promising strategy to preserve synaptic integrity and reduce long-term neurodegenerative sequelae after TBI.
ABSTRACT
Traumatic brain injury (TBI) is increasingly recognized not only as an acute mechanical insult but as a trigger of sustained neuroimmune activation that contributes to chronic neurodegeneration. 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-attack 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-dependent 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-term neurological sequelae after TBI.