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: 7118581
• 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/7118581
• 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.

应聘者描述(由申请人提供)：应聘者为医学博士/博士学位的临床神经科医生，其职业目标是研究创伤性脑损伤(TBI)易感性的遗传原因，重点研究痴呆症和阿尔茨海默病(AD)。华盛顿大学的大卫·霍尔茨曼博士建议在实验室接受科学指导培训，这将使候选人发展科学技能，成为一名独立的调查人员。在拟议的项目中将测试的中心假设如下：1)脑外伤导致大脑中淀粉样β蛋白(A-β)的产生增加和/或清除减少。2)在人类和转基因小鼠中，A-β浓度的增加对急性认知损害和AD的慢性病理都有显著的作用。3)阻断A-β的产生或增强其清除作用将减少脑损伤的认知和病理后遗症。4)载脂蛋白E e4基因(APOE4)对脑外伤易感性的增加和AD风险的增加主要是通过载脂蛋白E对A-β处理和代谢的影响而发生的。5)预防创伤性脑损伤后A-β的变化将减少APOE4对脑损伤后的不良后果。候选人建议使用双转基因小鼠来验证这些假设，这些小鼠同时产生载脂蛋白E和突变的淀粉样前体蛋白，从而在类似阿尔茨海默病的病理模式中沉积A-β。将与特雷西·麦金托什博士和菲尔·贝利博士合作，在这些小鼠身上进行实验性脑损伤。认知结果将使用Morris水迷宫和其他行为任务进行评估，并将对TBL诱导的损伤和AD样病理变化进行组织学分析。干预措施将包括注射抗A-β抗体，以增强A-β从大脑中的清除，以及注射伽马分泌酶抑制剂，以阻止A-β的产生。将对使用微透析在脑匀浆和活体中测量的A-β浓度进行机制研究，以深入了解相关的潜在机制。这项工作可能会为未来的脑损伤患者带来更好的治疗选择。