Injury-induced CTE-like pathology emerges in a human multicellular in vitro brain model and reveals mitochondrial and neurovascular regulation.
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease linked to repetitive mild head impacts, but no human-based experimental system exists to study injury-induced CTE-like pathology. Here, we establish a long-lived, human multicellular in vitro brain platform in which controlled mechanical injury induces key cellular features of CTE-like pathology. Injured cultures developed persistent tau phosphorylation, axonal degeneration, chronic inflammation, and metabolic dysfunction without widespread neuronal loss, consistent with progressive pathology rather than acute toxicity. To assess physiological relevance, we integrated transcriptomic profiles from the model with postmortem human CTE brain datasets. This analysis revealed striking convergence at the level of disease-associated modules and pathways, with endothelial cells emerging as critical contributors to CTE-like transcriptional programs. Using this human-based system, we further identified delayed mitochondrial dysfunction as a prominent and sustained feature of injury-induced pathology. Together, these findings establish the first human in vitro platform for studying injury-induced CTE-like pathology and identify neurovascular and mitochondrial regulation as central components of chronic neurodegeneration following repetitive mild brain injury.