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      A mouse Model of Focal Vascular Injury Induces Astrocyte Reactivity, Tau Oligomers, and Aberrant Behavior

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          Abstract

          Neuropsychiatric symptom development has become more prevalent with 270,000 blast exposures occurring in the past 10 years in the United States. How blast injury leads to neuropsychiatric symptomology is currently unknown. Preclinical models of blast-induced traumatic brain injury have been used to demonstrate blood-brain barrier disruption, degenerative pathophysiology, and behavioral deficits. Vascular injury is a primary effect of neurotrauma that can trigger secondary injury cascades and neurodegeneration. Here we present data from a novel scaled and clinically relevant mouse blast model that was specifically developed to assess the outcome of vascular injury. We look at the biochemical effects and behavioral changes associated with blast injury in young-adult male BALB/c mice. We report that blast exposure causes focal vascular injury in the Somatosensory Barrel Field cortex, which leads to perivascular astrocyte reactivity, as well as acute aberrant behavior. Biochemical analysis revealed that mild blast exposure also invokes tauopathy, neuroinflammation, and oxidative stress. Overall, we propose our model to be used to evaluate focal blood-brain barrier disruption and to discover novel therapies for human neuropsychiatric symptoms.

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          Proteopathic tau seeding predicts tauopathy in vivo.

          Brandon Holmes, Jennifer L Furman, Thomas E Mahan … (2014)
          Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼ 300 fM) and synuclein (∼ 300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.
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            Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.

            Rakez Kayed, Christian L Carranza, Barnaby Reeves … (2012)
            Neurofibrillary tangles (NFTs) are a pathological hallmark of Alzheimer's disease (AD); however, the relationship between NFTs and disease progression remains controversial. Analyses of tau animal models suggest that phenotypes coincide with accumulation of soluble aggregated tau species but not the accumulation of NFTs. The pathological role of prefilamentous tau aggregates, e.g., tau oligomeric intermediates, is poorly understood, in part because of methodological challenges. Here, we engineered a novel tau oligomer-specific antibody, T22, and used it to elucidate the temporal course and biochemical features of oligomers during NFT development in AD brain. We found that tau oligomers in human AD brain samples were 4-fold higher than those in the controls. We also revealed the role of oligomeric tau conformers in pretangles, neuritic plaques, and neuropil threads in the frontal cortex tissue from AD brains; this analysis uncovers a consistent code that governs tau oligomerization with regard to degree of neuronal cytopathology. These data are the first to characterize the role of tau oligomers in the natural history of NFTs, and they highlight the suitability of tau oligomers as therapeutic targets in AD and related tauopathies.
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              cis p-tau: early driver of brain injury and tauopathy blocked by antibody

              Asami Kondo, Koorosh Shahpasand, Rebekah Mannix … (2015)
              Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101622222
                Journal ID (pubmed-jr-id): 44404
                Journal ID (nlm-ta): Arch Neurosci
                Journal ID (iso-abbrev): Arch Neurosci
                Title: Archives of neuroscience
                ISSN (Print): 2322-3944
                ISSN (Electronic): 2322-5769
                Publication date Nihms-submitted: 11 May 2017
                Publication date (Electronic): 30 April 2017
                Publication date (Print): April 2017
                Publication date PMC-release: 26 July 2017
                Volume: 4
                Issue: 2
                Electronic Location Identifier: e44254
                Affiliations
                [1 ]Department of Pharmaceutical Sciences, West Virginia University School of Medicine, Morgantown, WV 26506-9530, USA
                [2 ]Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV 26506-9183, USA
                Author notes
                [* ] Corresponding author: Paul R. Lockman, Department of Pharmaceutical Sciences, West Virginia University School of Medicine, Morgantown, WV 26506-9530, USA, prlockman@ 123456hsc.wvu.edu
                Article
                Manuscript ID: NIHMS873914
                DOI: 10.5812/archneurosci.44254
                PMC ID: 5529099
                PubMed ID: 28758136
                SO-VID: fb496d4b-e5ca-4634-8e62-babfab61170d
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

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                Subject: Article

                Keywords: traumatic brain injury,blood-brain barrier disruption,astrocyte reactivity,tauopathy,neuropsychiatric behavior
                Data availability:
                Keywords: traumatic brain injury, blood-brain barrier disruption, astrocyte reactivity, tauopathy, neuropsychiatric behavior

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