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: 7463705
• 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/7463705
• 关键词: Acute; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Apolipoprotein E; Behavioral; Blood; Brain; Catheters; Cerebrospinal Fluid; Chronic; Clinical; Cognitive; Collaborations; Contralateral; Dementia; Deposition; Doctor of Philosophy; Enhancing Antibodies; Enzyme-Linked Immunosorbent Assay; Future; Genetic; Genotype; Goals; Hippocampus (Brain); Hour; Human; Impaired cognition; Implant; Intercellular Fluid; Intervention; Ipsilateral; Laboratories; Lead; Lesion; Measures; Mentors; Metabolism; Microdialysis; Monitor; Mus; Neurologist; Outcome; Outcome Measure; Pathology; Pattern; Predisposition; Production; Research Personnel; TBI Patients; Testing; Tg2576; Therapeutic; Training; Transgenic Mice; Traumatic Brain Injury; Treatment Protocols; Universities; Washington; Work; apolipoprotein E-3; career; controlled cortical impact; experience; gamma secretase; improved; in vivo; inhibitor/antagonist; insight; morris water maze; mutant; peptide A; prevent; programs; secretase; skills

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/博士培训的临床神经学家，其职业目标是调查创伤性脑损伤（TBI）易感性的遗传原因，重点是痴呆症和阿尔茨海默病（AD）。在华盛顿大学的大卫霍尔茨曼博士实验室进行指导性科学培训的建议时间将使候选人发展成为独立调查员的科学技能。在拟议项目期间将测试的中心假设如下：1）TBI导致大脑中淀粉样β肽（A-β）的产生增加和/或清除减少。2)由此产生的A-β浓度的增加对人类和转基因小鼠中的急性认知障碍和AD的慢性病理学都有显著贡献。3)阻断A-β产生或增强其清除将减少TBI的认知和病理后遗症。4)由载脂蛋白E e4基因型（APOE 4）赋予的对TBI的增加的脆弱性和AD的增加的风险主要通过apoE对A-β处理和代谢的影响而发生。5)预防TBI相关的A-β变化将减少TBI后APOE 4带来的不良后果。这位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和突变的淀粉样前体蛋白，因此在阿尔茨海默病样病理模式中存款A-β。将与Tracy McIntosh和Phil Bayly博士合作对这些小鼠进行实验性TBI。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。干预措施将包括给予抗A-β抗体，以增强A-β从大脑中的清除，并给予γ分泌酶抑制剂，以阻断A-β的产生。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，以深入了解相关的潜在机制。这项工作可能会在未来为TBI患者提供更好的治疗选择。

项目成果

Functional status after blast-plus-impact complex concussive traumatic brain injury in evacuated United States military personnel.

• DOI: 10.1089/neu.2013.3173
• 发表时间: 2014-05-15
• 期刊: Journal of neurotrauma
• 影响因子: 4.2
• 作者: MacDonald, Christine L;Johnson, Ann M;Brody, David L
• 通讯作者: Brody, David L

Amyloid-beta dynamics correlate with neurological status in the injured human brain.

淀粉样蛋白β动力学与受伤的人脑中的神经系统状况相关。

• DOI: 10.1126/science.1161591
• 发表时间: 2008-08-29
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Brody, David L.;Magnoni, Sandra;Schwetye, Kate E.;Spinner, Michael L.;Esparza, Thomas J.;Stocchetti, Nino;Zipfel, Gregory J.;Holtzman, David M.
• 通讯作者: Holtzman, David M.

Inhibition of JNK by a peptide inhibitor reduces traumatic brain injury-induced tauopathy in transgenic mice.

通过肽抑制剂对JNK的抑制作用可减少转基因小鼠中脑损伤引起的tauopathy。

• DOI: 10.1097/nen.0b013e3182456aed
• 发表时间: 2012-02
• 期刊: Journal of neuropathology and experimental neurology
• 影响因子: 3.2
• 作者: Tran HT;Sanchez L;Brody DL
• 通讯作者: Brody DL

Distinct temporal and anatomical distributions of amyloid-* and tau abnormalities following controlled cortical impact in transgenic mice.

转基因小鼠受控皮质影响后淀粉样蛋白-*和 tau 蛋白异常的独特时间和解剖分布。

• DOI: 10.1371/journal.pone.0025475
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Tran,HienT;Sanchez,Laura;Esparza,ThomasJ;Brody,DavidL
• 通讯作者: Brody,DavidL