Pathologic Thr¹⁷⁵ tau phosphorylation in CTE and CTE with ALS

Area of Science:

• Neuroscience
• Neuropathology
• Biochemistry

Background:

• Chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) are progressive neurodegenerative diseases.
• Tauopathies are characterized by abnormal tau protein phosphorylation.
• Glycogen synthase kinase-3β (GSK3β) is implicated in tau hyperphosphorylation.

Purpose of the Study:

• To investigate tau phosphorylation at Thr175 and Thr231 (pThr175 tau, pThr231 tau) and GSK3β activation in CTE and CTE-ALS.
• To determine if these pathological features are a consequence of traumatic brain injury (TBI).

Main Methods:

• Western blot analysis of tau isoforms in CTE cases.
• Immunohistochemistry for activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau in CTE, CTE-ALS, and control cases.
• Assessment of tau pathology and phospho-GSK3β in a rat model of moderate TBI.

Main Results:

• CTE and CTE-ALS exhibit all six tau isoforms.
• Activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau were found in neurons of CTE and CTE-ALS patients.
• Moderate TBI in rats induced tau pathology, including increased pThr175 tau and activated GSK3β.

Conclusions:

• Pathological tau phosphorylation at Thr175 and Thr231, along with GSK3β activation, are key features of CTE and CTE-ALS tauopathy.
• These pathological hallmarks can be recapitulated in an animal model following moderate TBI.