Amyloid-B and Apolipoprotein E in Traumatic Brain Injury

淀粉样蛋白 B 和载脂蛋白 E 在创伤性脑损伤中的作用

• 批准号: 6816211
• 负责人: David L Brody
• 金额: $ 14.41万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6816211
• 关键词: Alzheimer' s disease; amyloid proteins; apolipoprotein E; behavior test; brain injury; cerebrospinal fluid; cognition; enzyme linked immunosorbent assay; genetic susceptibility; genetically modified animals; genotype; hippocampus; laboratory mouse; microdialysis; molecular pathology; monoclonal antibody; neuropathology; neuropsychology; protease inhibitor; protein metabolism; protein structure function

DESCRIPTION (provided by applicant): The candidate is an MD/PhD trained clinical neurologist whose career goal is to investigate genetic causes of susceptibility to traumatic brain injury (TBI), with emphasis in dementia and Alzheimer's disease (AD). The proposed period of mentored scientific training in the laboratory of Dr. David Holtzman at Washington University will allow the candidate develop the scientific skills to become an independent investigator. The central hypotheses that will be tested during the proposed project are as follows: 1) TBI causes increased production and/or decreased clearance of the amyloid-beta peptide (A-beta) in the brain. 2) The resulting increase in A-beta concentration contributes significantly to both acute cognitive impairment and the chronic pathology of AD in humans and in transgenic mice. 3) Blocking A-beta production or enhancing its clearance will reduce cognitive and pathological sequelae of TBI. 4) The increased vulnerability to TBI and increased risk of AD conferred by the apolipoprotein E e4 genotype (APOE4) occurs largely via apoE's effects on A-beta handling and metabolism. 5) Preventing TBI related changes in A-beta will lessen the adverse outcomes conferred by APOE4 after TBI. The candidate proposes to test these hypotheses using double transgenic mice that produce both apoE and a mutant amyloid precursor protein, and hence deposit A-beta in Alzheimer's disease-like pathological patterns. Experimental TBI will be performed on these mice in collaboration with Drs. Tracy McIntosh and Phil Bayly. Cognitive outcomes will be assessed using the Morris water maze and other behavioral tasks, and histological analysis of TBl-induced lesions and AD-like pathological changes will be made. Interventions will include administration of an anti-A-beta antibody that enhances A-beta clearance from the brain and a gamma secretase inhibitor that blocks A-beta production. Mechanistic studies of A-beta concentrations measured in brain homogenates and in vivo using microdialysis will be performed to gain insight into the underlying mechanisms involved. This work may lead to improved therapeutic options for patients with TBI in the future.

描述（由申请人提供）：候选人是一名医学博士/博士训练的临床神经学家，其职业目标是研究创伤性脑损伤（TBI）易感性的遗传原因，重点是痴呆和阿尔茨海默病（AD）。在华盛顿大学David Holtzman博士的实验室进行一段时间的科学指导训练，将使候选人发展成为一名独立研究者的科学技能。在提议的项目中将测试的中心假设如下：1)TBI导致大脑中淀粉样蛋白-肽（a - β）的产生增加和/或清除减少。2)由此导致的a - β浓度升高对人和转基因小鼠AD的急性认知功能障碍和慢性病理均有显著影响。3)阻断a - β的产生或增强其清除可减少脑外伤的认知和病理后遗症。4)载脂蛋白e4基因型（APOE4）导致的TBI易感性增加和AD风险增加主要是通过apoE对a - β处理和代谢的影响发生的。5)预防脑外伤相关的a - β变化将减轻APOE4在脑外伤后带来的不良后果。候选人建议使用双转基因小鼠来测试这些假设，这些小鼠产生apoE和突变的淀粉样蛋白前体蛋白，因此在阿尔茨海默病样病理模式中沉积a - β。试验性脑外伤将在这些小鼠身上进行。特雷西·麦金托什和菲尔·贝利。认知结果将通过Morris水迷宫和其他行为任务进行评估，并对tbl引起的病变和ad样病理改变进行组织学分析。干预措施包括使用抗a - β抗体，增强大脑对a - β的清除，以及使用阻断a - β产生的分泌酶抑制剂。将进行脑匀浆和体内微透析测量a - β浓度的机制研究，以深入了解所涉及的潜在机制。这项工作可能会在未来改善TBI患者的治疗选择。