P2‐034: Mechanistic pathobiology of acute concussion, traumatic brain injury, and chronic traumatic encephalopathy in mouse models of blast neurotrauma and impact concussion
Year: 2015
Type: article
Abstract: Traumatic brain injury (TBI) is a leading cause of death and disability and Alzheimer's disease risk factor. We reported neuropathological evidence linking impact TBI with development of chronic traumatic encephalopathy (CTE), a tau protein neurodegenerative disease associated with head injury in athletes (McKee, Brain, 2013) and blast exposure in combat veterans (Goldstein, Science Transl Med, 2012). We reported that blast-exposed mice also develop CTE neuropathology (tau proteinopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration) that recapitulates CTE in humans. These abnormalities were accompanied by persistent neurophysiological deficits that correlated with cognitive deficits. CTE-linked neuropathology and deficits emerged within two weeks and persists for at least one month after blast exposure. We developed a impact neurotrauma mouse model that induces concussion with lateralized neurological signs, persistent neurophysiological deficits, and chronic neuropathology that recapitulates core features of impact neurotrauma in humans. C57BL/6 male mice were subjected to impact TBI and evaluated for concussion, CTE-linked neuropathology, ultrastructural and microvascular pathology, neuroinflammation, tau proteinopathy, hippocampal and cortical neurophysiology. Results: From impact and blast neurotrauma models were correlated with kinematic and biomechanical analyses obtained from high-speed videographic records with microsecond time resolution. Neuropathological examination of brains from mice subjected to concussive head injury exhibited early CTE neuropathology (tau proteinopathy, myelinated axonopathy, microvasculopathy, neuroinflammation, neurodegeneration) that recapitulates core features of early CTE in humans. We observed corresponding ultrastructural pathology (including profound changes in axonal, microvascular, blood-brain-barrier (BBB) structure and function) that were accompanied by slowed hippocampal axonal conduction and bilateral defects in prefrontal cortical synaptic plasticity. Kinematic and biomechanical analyses revealed predicted similarities and striking differences between blast and impact TBI that discriminate concussive from non-concussive head injury. Our results identify mechanisms of acute TBI that lead to concussion, post-concussive syndrome, and chronic sequelae, including CTE. This work reveals common and distinct pathways induced by different types of neurotrauma. The availability of murine models that accurately reproduce core features of acute and chronic effects of neurotrauma in humans opens new avenues for investigation of pathobiological mechanisms as well as translational development of diagnostics and therapeutics for TBI and CTE.
Source: Alzheimer s & Dementia
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2472780306