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: 6912822
• 负责人: David L Brody
• 金额: $ 15.28万
• 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/6912822
• 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）：候选人是一位接受过医学博士/博士学位培训的临床神经科医生，其职业目标是研究易受创伤性脑损伤（TBI）的遗传原因，重点是痴呆和阿尔茨海默氏病（AD）。拟议在华盛顿大学 David Holtzman 博士实验室进行的指导性科学培训将使候选人发展科学技能，成为一名独立研究者。在拟议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-β 肽 (A-β) 的产生增加和/或清除减少。 2) 由此产生的 A-β 浓度增加显着导致人类和转基因小鼠的急性认知障碍和 AD 的慢性病理学。 3) 阻断A-β的产生或增强其清除率将减少TBI的认知和病理后遗症。 4) 载脂蛋白 E 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 处理和代谢的影响而发生的。 5) 预防 TBI 相关的 A-β 变化将减轻 TBI 后 APOE4 带来的不良后果。该候选人提议使用双转基因小鼠来测试这些假设，这些转基因小鼠同时产生 apoE 和突变淀粉样前体蛋白，从而在类似阿尔茨海默病的病理模式中沉积 A-β。将与 Drs 合作对这些小鼠进行实验性 TBI。特雷西·麦金托什和菲尔·贝利。将使用 Morris 水迷宫和其他行为任务评估认知结果，并对 TBl 诱导的病变和 AD 样病理变化进行组织学分析。干预措施包括施用抗 A-β 抗体（增强 A-β 从大脑中的清除）和γ分泌酶抑制剂（阻止 A-β 产生）。将使用微透析对脑匀浆和体内测量的 A-β 浓度进行机制研究，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。