Blast-induced traumatic brain injury (blast TBI) is considered the signature injury of current military conflicts. Veterans exposed to blast TBI suffer concussions and neurological deficits, and are at increased risk for developing chronic neurological disorders including chronic traumatic encephalopathy and Alzheimer's disease (AD). Rehabilitation of blast-injured Veterans and prevention of chronic neuropathology is an area of medical research in need of intensive investigation because long-term effects of blast TBI are currently unknown and there are no treatments for improving long-term functional recovery after blast TBI. Our preliminary studies demonstrate that experimental blast TBI in mice impairs cognitive, vestibulomotor and sensory (visual) function, and these deficits are accompanied by changes in amyloid-? (A?) and tau proteins which comprise the hallmark neuropathology of AD. We propose to use the transgenic APPswe,PSEN1dE9 mouse model, which recapitulates several aspects of age- and injury-induced A? pathology, to test the hypothesis that repetitive mild blast injury accelerates the onset and/or aggravates the onset and progression of A? accumulation and induces excessive tau phosphorylation (p-tau), exacerbating synaptic loss and functional impairment. These changes will be examined in relation to performance on spatial memory and vestibulomotor tasks during the chronic rehabilitation period after blast TBI. We also hypothesize that blast injury impairs retinal function, and propose to evaluate if such deficit could serve as an early diagnostic indicator of blast-induced damage to the brain. Additional biomarker analyses of diagnostic and potential prognostic values will include diffusion tensor imaging (DTI) and measurements of A? and p-tau concentration in cerebrospinal fluid (csf) and plasma. These studies will provide the framework for another major goal of this proposal, which is to test the therapeutic value of simvastatin, an FDA- approved drug currently in use for treatment of hypercholesterolemia and markedly effective in improving outcome in several models of brain injury. We will first characterize A? and p-tau pathology and functional (visual, vestibulomotor, cognitive) deficits during the chronic recovery phase (3, 6, 9, and 12 months) after single or repetitive mild (20 psi) grade blast exposure in the APPswe,PSEN1dE9 and C57Bl/6 wild type mice (Aim 1). The second major goal is to assess whether acute, transient (3 month) or continuous chronic (duration of survival period) daily simvastatin administration will prevent early onset of, and/or reduce, A? and p-tau pathology and improve functional recovery after blast injury in APPswe,PSEN1dE9 mice compared to C57Bl/6 wild type mice evaluated 3, 6, 9, and 12 months after injury (Aim 2). Thirdly, we will determine how chronic sequelae of blast injury, with or without simvastatin intervention, correlate with axonal pathology and changes in brain connectivity (by DTI) and levels of A? and p-tau in csf and plasma, thus providing valuable diagnostic and/or prognostic tests to be used together with the assessments of visual and memory function in blast TBI (Aim 3). Longitudinal assessments of vestibulomotor and visual function will be performed at 3, 6, 9, and 12 months after blast injury. Cognitive function will be tested at each time point prior to DTI imaging, csf and plasma collection, and sacrifice, followed by Ab, p-tau, APP, BDNF and other neurotrophin molecule analyses, quantification of plaque load, cell number, synapse density, and microglia/astrocyte reactivity. Collectively, these studies will determine whether blast TBI can accelerate and exacerbated chronic neurodegenerative changes typical of AD and CTE, and will determine the potential value of the proposed functional diagnostic and therapy approaches for their translation into clinical evaluation and treatment of blast-injured Veterans.
Blast injury is the signature injury of current military conflicts. Veterans exposed to blast that injures the brain suffer neurological deficits and may be at an increased risk for developing chronic neurodegenerative disorders such as Alzheimer's disease (AD), which is particularly relevant to the aging veteran population. We propose to characterize the long-term neuropathological changes caused by blast injury and the effect of a novel therapy on these changes. The proposed therapy has the potential to improve rehabilitation after blast injury and to reduce the chronic post-injury pathological changes that may confer risk of developing AD later in life. This therapy, if successful in the proposed experimental model, can be rapidly translated to the clinical setting to improve health and quality of life of brain injured veterans, and to reduce the considerable burden on the VA healthcare system.
|Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E (2017) Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders. Ageing Res Rev 34:51-63|