MECHANISMS UNDERLYING AMYLOID-BETA AND TAU PATHOLOGIES FOLLOWING TBI

TBI 后 β 淀粉样蛋白和 TAU 病理学的潜在机制

• 批准号: 8269685
• 负责人: David L Brody
• 金额: $ 32.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269685
• 关键词: Acute; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Antibodies; Applications Grants; Behavior assessment; Behavioral; Brain; Caspase; Caspase Inhibitor; Cause of Death; Cells; Cleaved cell; Cognitive; Contralateral; Dementia; Deposition; Enzymes; Future; Genetic; Genetically Engineered Mouse; Goals; Hippocampus (Brain); Hour; Human; Injury; Knock-out; Knockout Mice; Life; Mediator of activation protein; Memory; Methods; Microdialysis; Military Personnel; Modeling; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Outcome; Pathologic Processes; Pathology; Patients; Peptide Hydrolases; Peptides; Performance; Play; Process; Production; Proteins; Relative (related person); Research Personnel; Risk; Role; Testing; Therapeutic; Thinking; Time; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; adverse outcome; assault; base; beta-site APP cleaving enzyme 1; caspase-3; clinically relevant; controlled cortical impact; design; disability; effective therapy; falls; fimbria; improved; inhibitor/antagonist; injured; interest; meetings; mouse model; neurotoxic; operation; prevent; protein expression; research study; secretase; success; tau Proteins; tau mutation; therapeutic development; therapeutic target; vehicular accident

PROJECT SUMMARY Traumatic brain injury (TBI) is a major cause of death and disability, especially among young people. Pathological processes involving the amyloid-beta (A¿) peptide and tau protein are accelerated by acute TBI. Moderate to severe TBI substantially increases the risk of dementia of the Alzheimer type later in life. A¿ deposition is a major pathological hallmark of Alzheimer disease (AD) and pathological tau abnormalities are seen in AD and many other neurodegenerative conditions. These A¿ and tau abnormalities may also contribute to short-term adverse outcomes, as some forms of these proteins can have immediately neurotoxic effects. Additional studies have found that A¿ can cause or accelerate tau pathology under some conditions, thus A¿ may play a central role in both pathologies. However, the mechanisms underlying A¿ and tau abnormalities following TBI are incompletely understood, in large part due to the lack of an appropriate small animal model. Preliminary results indicate that experimental controlled cortical impact TBI in 3xTg-AD mice results in intra-axonal A¿ deposition in the injured fimbria and accelerated tau pathology in the contralateral hippocampus within 24 hours of injury. 3xTg-AD mice produce both human A¿ and human tau with mutations that accelerate pathology, but in our experiments they were injured at young ages before significant neuropathological abnormalities are normally present. The long-term objective of the proposed project is to test the central hypothesis that A¿ is a key mediator of adverse behavioral and neuropathological outcomes following TBI. The specific aims are 1) to determine the mechanisms responsible for accelerated A¿ deposition following TBI in the 3xTg-AD mouse model, 2) to determine if TBI-induced A¿ overproduction plays a causal role in tau hyperphosphorylation and accumulation, and 3) to determine the effects of TBI-induced acute A¿ accumulation on sub-acute outcomes including behavioral performance axonal injury, neuronal cell loss, and tau pathology. Methods used will include a) colocalization studies of amyloid precursor protein (APP) and A¿ with several proteolytic enzymes thay may cleave APP to produce A¿. b) pharmacological or genetic inhibition of several potential A¿ producing enzymes, c) analysis of tau pathology in several lines of transgenic mice with and without human A¿, d) assessment of behavioral performance in mice treated with A¿-targeted therapeutics or with genetic manpulations that eliminate A¿ production. If successful, these experiments will result in an improved understanding of the mechanisms underlying A¿ and tau abnormalities following TBI. This may facilitate development of therapeutic strategies targeting A¿ and tau, which could ultimately improve outcomes and reduce the subsequent risk of dementia and adverse cognitive outcomes in TBI patients.

项目摘要 创伤性脑损伤（TBI）是死亡和残疾的主要原因，特别是在年轻人中。 涉及淀粉样蛋白-β（A）肽和tau蛋白的病理过程被急性TBI加速。 中度至重度TBI大大增加了以后生活中阿尔茨海默型痴呆的风险。A？ 沉积是阿尔茨海默病（AD）的主要病理学标志，并且病理性tau异常是阿尔茨海默病（AD）的主要病理学标志。 在AD和许多其他神经退行性疾病中可见。这些A和tau异常也可能 导致短期不良后果，因为这些蛋白质的某些形式可以立即产生神经毒性 方面的影响.其他研究发现，在某些条件下，A？可以引起或加速tau病理， 因此，A？可能在这两种病理中起着核心作用。然而，A和tau的潜在机制 TBI后的异常不完全了解，在很大程度上是由于缺乏适当的小 动物模型初步结果表明，在3xTg-AD小鼠中，实验性对照皮质撞击TBI 导致受损伞部的轴突内A？沉积，并加速对侧的tau病理 海马损伤24小时内。3xTg-AD小鼠产生具有突变的人A？和人tau 但在我们的实验中，他们在年轻时就受伤了， 神经病理学异常通常存在。 拟议项目的长期目标是测试中心假设，即A是一个关键 TBI后不良行为和神经病理学结果的介导者。具体目标是：（1） 确定3xTg-AD小鼠TBI后加速A？沉积的机制 模型，2）确定TBI诱导的A？过度产生是否在tau蛋白过度磷酸化中起因果作用， 蓄积，以及3）确定TBI诱导的急性A？蓄积对亚急性结局的影响 包括行为表现轴突损伤、神经元细胞损失和tau病理学。使用的方法将 包括a）淀粉样前体蛋白（APP）和A？与几种蛋白水解酶共定位研究 它们可以裂解APP产生A？。B）药理学或遗传学抑制几种潜在的A？产生 酶，c）在具有和不具有人A？的几个转基因小鼠系中的tau病理学分析，d） 评估用A？靶向治疗剂或遗传治疗剂治疗的小鼠的行为表现 #21453;，以消除生产？如果成功的话，这些实验将改善 理解TBI后A？和tau异常的潜在机制。这可以促进 开发针对A和tau的治疗策略，最终可以改善结果， 降低TBI患者痴呆和不良认知结果的后续风险。