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: 7634321
• 负责人: David L Brody
• 金额: $ 33.25万
• 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/7634321
• 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; Operative Surgical Procedures; 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; abeta accumulation; assault; base; beta amyloid pathology; beta-site APP cleaving enzyme 1; caspase-3; clinically relevant; controlled cortical impact; design; disability; effective therapy; falls; fimbria; genetic manipulation; improved; inhibitor/antagonist; injured; interest; meetings; mouse model; neurotoxic; prevent; protein expression; public health relevance; research study; secretase; success; tau Proteins; tau mutation; therapeutic development; therapeutic target; vehicular accident

DESCRIPTION (provided by applicant): 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 manipulations 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. PUBLIC HEALTH RELEVANCE: Traumatic brain injury- such as from motor vehicle accidents, falls, assault, or military operations- is a common cause of impaired thinking and memory immediately after the injury and increases the chances of developing Alzheimer's disease later in life. The goal of this project is to use genetically engineered mice to improve our understanding of the causes of these thinking and memory problems and increased risk of Alzheimer's disease. If successful, the results of the project may point to ways to develop effective treatments to prevent or reverse these problems in the future.

描述（由申请人提供）：创伤性脑损伤（TBI）是死亡和残疾的主要原因，尤其是在年轻人中。急性 TBI 会加速涉及淀粉样蛋白 - β (A¿) 肽和 tau 蛋白的病理过程。中度至重度 TBI 会显着增加晚年患阿尔茨海默型痴呆的风险。沉积是阿尔茨海默病 (AD) 的主要病理标志，病理性 tau 异常可见于 AD 和许多其他神经退行性疾病。这些 A¿ 和 tau 蛋白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能会立即产生神经毒性作用。其他研究发现，A¿ 在某些条件下可以引起或加速 tau 蛋白病理，因此 A 可能在这两种病理中发挥核心作用。然而，TBI 后 A¿ 和 tau 蛋白异常的机制尚不完全清楚，很大程度上是由于缺乏合适的小动物模型。初步结果表明，对 3xTg-AD 小鼠进行实验控制的皮质冲击 TBI 会导致受伤的伞部轴突内 A¿ 沉积，并在受伤 24 小时内加速对侧海马的 tau 病理。 3xTg-AD 小鼠产生人类 A¿ 和人类 tau 蛋白，其突变会加速病理学，但在我们的实验中，它们在通常出现显着神经病理学异常之前就在年轻时受伤。该项目的长期目标是检验中心假设，即 A¿ 是 TBI 后不良行为和神经病理结果的关键介质。具体目标是 1) 确定 3xTg-AD 小鼠模型中 TBI 后加速 A¿ 沉积的机制，2) 确定 TBI 诱导的 A¿ 过量产生是否在 tau 过度磷酸化和积累中起因果作用，3) 确定 TBI 诱导的急性 A¿ 积累对亚急性结果的影响，包括行为表现轴突损伤、神经元细胞丢失和 tau 病理学。使用的方法包括：a) 淀粉样前体蛋白 (APP) 和 A¿ 与几种可能裂解 APP 产生 A¿ 的蛋白水解酶的共定位研究，b) 对几种潜在的 A¿ 产生酶的药理学或遗传抑制，c) 具有和不具有人类 A¿ 的几个转基因小鼠品系的 tau 病理学分析，d) 评估用 A¿ 靶向治疗的小鼠的行为表现 治疗或基因操作可以消除 A¿ 的产生。如果成功，这些实验将有助于更好地理解 TBI 后 A¿ 和 tau 蛋白异常的机制。这可能有助于开发针对 A¿ 和 tau 的治疗策略，最终可以改善 TBI 患者的结果并降低随后发生痴呆和不良认知结果的风险。公共卫生相关性：创伤性脑损伤（例如机动车事故、跌倒、袭击或军事行动）是受伤后思维和记忆受损的常见原因，并增加了以后患阿尔茨海默病的机会。该项目的目标是利用基因工程小鼠来提高我们对这些思维和记忆问题以及阿尔茨海默病风险增加的原因的理解。如果成功，该项目的结果可能会指出开发有效治疗方法以预防或扭转未来这些问题的方法。