Chronic effects of blast injury: analyses of Alzheimer related pathology

描述(由申请人提供)： 冲击波致颅脑损伤被认为是当前军事冲突中的标志性损伤。暴露在冲击波脑损伤下的退伍军人会出现脑震荡和神经功能障碍，并有更高的风险发展为慢性神经疾病，包括慢性创伤性脑病和阿尔茨海默病(AD)。退伍军人冲击伤的康复和慢性神经病理的预防是一个需要深入研究的医学研究领域，因为冲击伤的长期影响目前尚不清楚，而且还没有改善冲击伤后长期功能恢复的治疗方法。我们的初步研究表明，实验性冲击性脑损伤会损害小鼠的认知、前庭运动和感觉(视觉)功能，这些缺陷伴随着淀粉样蛋白(A)和tau蛋白的变化，这两种蛋白构成了AD的标志性神经病理。我们建议使用转基因APPswe，PSEN1dE9小鼠模型，该模型概括了年龄和损伤诱导的A？病理的几个方面，以检验以下假设：反复轻度冲击伤加速和/或加重A？的发生和发展，并诱导过度的tau磷酸化(p-tau)，加剧突触丢失和功能损害。这些变化将与冲击性脑损伤后慢性康复期的空间记忆和前庭运动任务的表现相关联。我们还假设冲击伤会损害视网膜功能，并建议评估这种缺陷是否可以作为冲击性脑损伤的早期诊断指标。对诊断和潜在预后价值的其他生物标志物分析将包括扩散张量成像(DTI)和测量脑脊液(CSF)和血浆中的A？和p-tau浓度。这些研究将为这项提案的另一个主要目标提供框架，即测试辛伐他汀的治疗价值，辛伐他汀是FDA批准的一种药物，目前正用于治疗高胆固醇血症，在几种脑损伤模型中明显有效地改善预后。我们将首先描述APPsWE、PSEN1dE9和C57BL/6野生型小鼠在单次或重复轻度(20psi)冲击波暴露后慢性恢复期(3、6、9和12个月)的A和p-tau病理和功能(视觉、前庭运动、认知)缺陷(目标1)。第二个主要目标是评估APPsWE、PSEN1dE9小鼠在冲击伤后3个月、6个月、9个月和12个月接受急性、短暂(3个月)或持续慢性(生存期)辛伐他汀治疗是否能预防和/或减轻A？和p-tau病理并改善功能恢复(目标2)。第三，我们将确定冲击伤的慢性后遗症，无论有没有辛伐他汀干预，如何与轴突病理和脑连通性的变化(通过DTI)以及脑脊液和血浆中A？和p-tau的水平相关联，从而提供有价值的诊断和/或预后测试，与冲击性脑损伤视觉和记忆功能的评估(目标3)一起使用。冲击伤后3、6、9和12个月将进行前庭运动和视觉功能的纵向评估。认知功能将是 在DTI成像、脑脊液和血浆采集及处死前的每个时间点进行检测，随后进行抗体、p-tau、APP、BDNF和其他神经营养因子分子分析，定量斑块负荷、细胞数量、突触密度和小胶质细胞/星形胶质细胞的反应性。总的来说，这些研究 将确定BLAST TBI是否可以加速和加剧AD和CTE典型的慢性神经退行性改变，并将确定拟议的功能诊断和治疗方法的潜在价值，将其转化为临床评估和治疗冲击伤退伍军人。

DESCRIPTION (provided by applicant): 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.