Pathologic Thr(175) tau phosphorylation in CTE and CTE with ALS

OBJECTIVE: To investigate whether chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) exhibit features previously observed in other tauopathies of pathologic phosphorylation of microtubule-associated protein tau at Thr(175) (pThr(175) tau) and Thr(231) (pThr(231) tau), and glycogen synthase kinase–3β (GSK3β) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI). METHODS: Tau isoform expression was assayed by western blot in 6 stage III CTE cases. We also used immunohistochemistry to analyze 5 cases each of CTE, CTE-ALS, and 5 controls for expression of activated GSK3β, pThr(175) tau, pThr(231) tau, and oligomerized tau within spinal cord tissue and hippocampus. Using a rat model of moderate TBI, we assessed tau pathology and phospho-GSK3β expression at 3 months postinjury. RESULTS: CTE and CTE-ALS are characterized by the presence of all 6 tau isoforms in both soluble and insoluble tau isolates. Activated GSK3β, pThr(175) tau, pThr(231) tau, and oligomerized tau protein expression was observed in hippocampal neurons and spinal motor neurons. We observed tau neuronal pathology (fibrillar inclusions and axonal damage) and increased levels of pThr(175) tau and activated GSK3β in moderate TBI rats. CONCLUSIONS: Pathologic phosphorylation of tau at Thr(175) and Thr(231) and activation of GSK3β are features of the tauopathy of CTE and CTE-ALS. These features can be replicated in an animal model of moderate TBI.