Tau Immunophenotypes in chronic traumatic encephalopathy recapitulate those of aging and Alzheimer’s disease

Arena, J. D., Smith, D. H., Lee, E. B., Gibbons, G. S., Irwin, D. J., Robinson, J. L., Lee, V. M.-Y., Trojanowski, J. Q., Stewart, W. and Johnson, V. E. (2020) Tau Immunophenotypes in chronic traumatic encephalopathy recapitulate those of aging and Alzheimer’s disease. Brain, 143(5), (doi: 10.1093/brain/awaa071)

Abstract

Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer’s disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer’s disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer’s disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer’s disease and ageing may rest solely on the pattern and distribution of pathology.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stewart, Dr William
• Authors: Arena, J. D., Smith, D. H., Lee, E. B., Gibbons, G. S., Irwin, D. J., Robinson, J. L., Lee, V. M.-Y., Trojanowski, J. Q., Stewart, W., and Johnson, V. E.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Brain
• Publisher: Oxford University Press
• ISSN: 0006-8950
• ISSN (Online): 1460-2156
• Published Online: 11 May 2020
• Copyright Holders: Copyright © The Author(s) (2020)
• First Published: First published in Brain 143(5):1572-1587
• Publisher Policy: Reproduced in accordance with the publisher copyright policy

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
307485		COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI	William Stewart	National Institutes of Health (NIH)	u54ns115322	Institute of Neuroscience & Psychology
174222		Characterising amyloid pathologies after traumatic brain injury	William Stewart	National Institutes of Health (NIH)	2R01NS038104-15A1	Institute of Neuroscience & Psychology