Tau Oligomers Derived from Traumatic Brain Injury Cause Cognitive Impairment and Accelerate Onset of Pathology in Htau Mice

• Published in: Journal of neurotrauma Vol. 33; no. 22; pp. 2034 - 2043
• Main Authors: Gerson, Julia, Castillo-Carranza, Diana L, Sengupta, Urmi, Bodani, Riddhi, Prough, Donald S, DeWitt, Douglas S, Hawkins, Bridget E, Kayed, Rakez
• Format: Journal Article
• Language: English
• Published: United States Mary Ann Liebert, Inc 15.11.2016
• Subjects: Animals; Brain Injuries, Traumatic - metabolism; Brain Injuries, Traumatic - pathology; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Humans; Male; Mice; Mice, Transgenic; Neurodegeneration; Original; Pathogenesis; Proteins; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques - instrumentation; tau Proteins - administration & dosage; tau Proteins - biosynthesis; tau Proteins - toxicity; Toxicity; Traumatic brain injury; neurodegeneration; traumatic brain injury; tau oligomers
• ISSN: 0897-7151; 1557-9042
• DOI: 10.1089/neu.2015.4262

Tau aggregation is a pathological feature of numerous neurodegenerative disorders and has also been shown to occur under certain conditions of traumatic brain injury (TBI). Currently, no effective treatments exist for the long-term effects of TBI. In some cases, TBI not only induces cognitive changes immediately post-injury, but also leads to increased incidence of neurodegeneration later in life. Growing evidence from our lab and others suggests that the oligomeric forms of tau initiate the onset and spread of neurodegenerative tauopathies. Previously, we have shown increased levels of brain-derived tau oligomers in autopsy samples from patients diagnosed with Alzheimer's disease. We have also shown similar increases in tau oligomers in animal models of neurodegenerative diseases and TBI. In the current study, we evaluated the presence of tau oligomers in blast-induced TBI. To test the direct impact of TBI-derived tau oligomer toxicity, we isolated tau oligomers from brains of rats that underwent either a blast- or a fluid percussion injury-induced TBI. Oligomers were characterized biochemically and morphologically and were then injected into hippocampi of mice overexpressing human tau (Htau). Mice were cognitively evaluated and brains were collected for immunological analysis after testing. We found that tau oligomers form as a result of brain injury in two different models of TBI. Additionally, these oligomers accelerated onset of cognitive deficits when injected into brains of Htau mice. Tau oligomer levels increased in the hippocampal injection sites and cerebellum, suggesting that tau oligomers may be responsible for seeding the spread of pathology post-TBI. Our results suggest that tau oligomers play an important role in the toxicity underlying TBI and may be a viable therapeutic target.