title: Tau Oligomers Derived from Traumatic Brain Injury Cause Cognitive Impairment and Accelerate Onset of Pathology in Htau Mice.
abstract: 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.
authors.affiliation: 1 Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch , Galveston, Texas.|2 Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch , Galveston, Texas.
authors.forename: Julia
authors.initials: J
authors.lastname: Gerson
authors.affiliation: 1 Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch , Galveston, Texas.|2 Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch , Galveston, Texas.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Castillo-Carranza
authors.affiliation: 1 Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch , Galveston, Texas.|2 Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch , Galveston, Texas.
authors.forename: Urmi
authors.initials: U
authors.lastname: Sengupta
authors.affiliation: 1 Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch , Galveston, Texas.|2 Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch , Galveston, Texas.
authors.forename: Riddhi
authors.initials: R
authors.lastname: Bodani
authors.affiliation: 3 Department of Anesthesiology, University of Texas Medical Branch , Galveston, Texas.|5 Moody Project for Translational Traumatic Brain Injury Research, Department of Anesthesiology, University of Texas Medical Branch , Galveston, Texas.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Prough
authors.affiliation: 3 Department of Anesthesiology, University of Texas Medical Branch , Galveston, Texas.|5 Moody Project for Translational Traumatic Brain Injury Research, Department of Anesthesiology, University of Texas Medical Branch , Galveston, Texas.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: DeWitt
authors.affiliation: 3 Department of Anesthesiology, University of Texas Medical Branch , Galveston, Texas.|4 Sealy Center for Vaccine Development, University of Texas Medical Branch , Galveston, Texas.|5 Moody Project for Translational Traumatic Brain Injury Research, Department of Anesthesiology, University of Texas Medical Branch , Galveston, Texas.
authors.forename: Bridget E
authors.initials: BE
authors.lastname: Hawkins
authors.affiliation: 1 Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch , Galveston, Texas.|2 Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch , Galveston, Texas.|4 Sealy Center for Vaccine Development, University of Texas Medical Branch , Galveston, Texas.|5 Moody Project for Translational Traumatic Brain Injury Research, Department of Anesthesiology, University of Texas Medical Branch , Galveston, Texas.
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013238:Stereotaxic Techniques / Q000295:instrumentation; D016875:tau Proteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000633:toxicity*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins
keywords: neurodegeneration; tau oligomers; traumatic brain injury