Pathologic Thr¹⁷⁵ tau phosphorylation in CTE and CTE with ALS

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 Thr¹⁷⁵ (pThr¹⁷⁵ tau) and Thr²³¹ (pThr²³¹ tau), and glycogen synthase kinase-3β (GSK3β) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI).

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, pThr¹⁷⁵ tau, pThr²³¹ 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.

CTE and CTE-ALS are characterized by the presence of all 6 tau isoforms in both soluble and insoluble tau isolates. Activated GSK3β, pThr¹⁷⁵ tau, pThr²³¹ 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 pThr¹⁷⁵ tau and activated GSK3β in moderate TBI rats.

Pathologic phosphorylation of tau at Thr¹⁷⁵ and Thr²³¹ 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.