Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that develops after repetitive head injury. Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfu...

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Bibliographic Details
Published in:Journal of neuropathology and experimental neurology 2016-01, Vol.75 (1), p.19-34
Main Authors: Kanaan, Nicholas M., Cox, Kristine, Alvarez, Victor E., Stein, Thor D., Poncil, Sharra, McKee, Ann C.
Format: Article
Language:English
Subjects:
Brain Injuries - genetics
Brain Injuries - metabolism
Brain Injuries - pathology
Chronic Disease
Female
Frontal Lobe - metabolism
Frontal Lobe - pathology
Humans
Male
Original
Phosphorylation - physiology
Protein Conformation
tau Proteins - genetics
tau Proteins - metabolism
Tauopathies - genetics
Tauopathies - metabolism
Tauopathies - pathology
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Summary:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that develops after repetitive head injury. Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD). Additionally, phosphorylation at serine 422 in tau occurs early and correlates with cognitive decline in patients with Alzheimer disease (AD). We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE. Notably, the TauC3 epitope, which is abundant in AD, was relatively sparse in CTE. Together, these results provide the first description of PAD exposure, TOC1 reactive oligomers, phosphorylation of S422, and TauC3 truncation in the tau pathology of CTE.
ISSN:0022-3069
1554-6578
DOI:10.1093/jnen/nlv001