Tau seeding in chronic traumatic encephalopathy parallels disease severity.

Chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, is associated with behavioral, mood and cognitive impairment, including dementia. Tauopathies are neurodegenerative diseases whose neuropathological phenotypes are characterized by distinct histopathologic features of tau pathology, which progressively deposit throughout the brain. In certain tauopathies, especially Alzheimer's disease (AD), tau deposition appears to follow brain network connections. Experimental evidence suggests that the progression of tau pathology in humans, mouse and cell models could be explained by tau seeds that adopt distinct conformations and serve as templates for their own amplification to mediate transcellular propagation of pathology. Tau seeds are efficiently detected by the induction of aggregation in cell-based "biosensors" that express tau repeat domain (RD) with a disease-associated mutation (P301S) fused to complementary fluorescent protein tags (cyan and yellow fluorescent protein). Biosensors enable quantification of tau seeding in fixed and fresh-frozen brain tissue. Phospho-tau deposition in CTE follows progressive stages (I-IV), but the relationship of seeding to this deposition is unclear. We have used an established biosensor assay to independently quantify tau seeding as compared to AT8 phospho-tau histopathology in thin sections of fixed tissues of 11 brain regions from 27 patients with CTE, 5 with other tauopathies, and 5 negative controls. In contrast to prior studies of AD, we detected tau seeding late in the course of CTE (predominantly stages III and IV). It was less anatomically prevalent than AT8-positive inclusions, which were relatively widespread. We especially observed seeding in the limbic system (amygdala, thalamus, basal ganglia), which may explain the dominant cognitive and behavior impairments that characterize CTE.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)