Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer's Disease

血管对痴呆症的影响和阿尔茨海默病的遗传风险因素

• 批准号: 10621697
• 负责人: ARTHUR W TOGA
• 金额: $ 323.16万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621697
• 关键词: APP-PS1; Acceleration; Address; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Astrocytes; Behavior; Behavior assessment; Behavioral; Biological Markers; Biometry; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain imaging; California; Cells; Cerebrovascular Circulation; Clinic; Clinical; Cognitive; Collaborations; Complement; Data; Dementia; Disease Progression; Enrollment; Environment; Experimental Designs; Genetic Risk; Goals; Homozygote; Human; Huntington Disease; Image; Impaired cognition; Informatics; Institution; Knock-in; Leadership; Longitudinal Studies; LoxP-flanked allele; Magnetic Resonance Imaging; Measurement; Measures; Medical Research; Molecular; Molecular Medicine; Mus; Nerve Degeneration; Neurology; Neuronal Dysfunction; Neurons; Paper; Participant; Pathogenesis; Pathology; Pericytes; Persons; Plasma; Positron-Emission Tomography; Prevention; Prognostic Marker; Proteomics; Psychology; Research; Research Institute; Research Personnel; Research Project Grants; Resources; Risk; Role; Science; Scotland; Signal Transduction; Site; Source; Structure; Sum; Synapses; System; Technology; Testing; Thinking; Universities; Vascular Dementia; Vascular Diseases; Washington; Work; Writing; activated Protein C; analog; apolipoprotein E-3; apolipoprotein E-4; blood-brain barrier permeabilization; cerebrovascular; clinical center; cognitive testing; dementia risk; effective therapy; follow-up; genetic risk factor; imaging modality; mild cognitive impairment; multidisciplinary; mutant; neurogenetics; neuroimaging; neurovascular; neurovascular unit; new therapeutic target; participant enrollment; pre-clinical; programs; protein protein interaction; recruit; screening; specific biomarkers; success; tau Proteins; therapeutic target

OVERALL – PROJECT SUMMARY/ABSTRACT This is a continuing multi-disciplinary program on VASCULAR CONTRIBUTIONS TO DEMENTIA AND GENETIC RISK FACTORS FOR ALZHEIMER’S DISEASE with multiple projects, cores, institutions and 24 investigators from the Zilkha Neurogenetic Institute, Stevens Neuroimaging and Informatics Institute, Alzheimer’s Disease Research Center (ADRC), University of Southern California (USC), LA, CA; Washington University Knight ADRC, Dept. of Neurology, Washington University, St. Louis, MO; Huntington Medical Research Institutes, Pasadena, CA; Banner Alzheimer’s Institute and Mayo Clinic, AZ; Dept. of Psychology, UC Irvine; Dept. of Molecular Medicine, Scripps Research Institute ; and Centre for Clinical Brain Sciences, Univ. of Edinburgh, Scotland. The overall goal of the program is to test the ‘neurovascular hypothesis’ of AD and establish whether the neurovasculature has a major role in the pathogenesis of early cognitive decline, and therefore could be a key new therapeutic target to treat early cognitive impairment, dementia and early AD. The program includes continuing participation by accomplished investigators in all aspects of this research plan. The collective expertise of the investigators, overall environment, preliminary results, and experimental design for each of the projects and supporting cores produced considerable success of this program over the past 4 years. During this period we collected vast amounts of data, analyzed them and wrote an impressive number of high impact papers. Our renewal is concentrated on apolipoprotein E (APOE), the major genetic risk factor for AD. We propose longitudinal studies in APOE4 carriers (ε3/ε4; ε4/ε4) that are at high genetic risk for AD and develop early cerebrovascular changes including breakdown in the blood-brain barrier (BBB) relative to APOE3 homozygotes (ε3/ε3) that are at a lower risk for AD and develop slower cerebrovascular changes. We anticipate following 402 APOE4 carriers and 465 APOE3 homozygotes (ages 45-90) initially enrolled as cognitively unimpaired (CU, 75%) or with mild cognitive impairment (MCI, 25%). This includes 510 participants enrolled in the program during the initial P01 period, and 360 new participants to be recruited during the first 3 years of the renewal. In these APOE4 and APOE3 participants we will apply cutting-edge molecular and imaging methods to study the contribution of BBB/vascular dysfunction to preclinical cognitive decline, loss of brain connectivity, neurodegeneration, and longitudinal clinical progression along the continuum from CU to MCI, and MCI to dementia, in relation to Aβ and tau AD biomarker abnormalities (CSF, PET). Experimentally, we will study how BBB/vascular dysfunction relates to synaptic and neuronal dysfunction and behavior in APOE (knock-in)flox/flox (KIF) mice with and without apoE deletion from astrocytes and pericytes (key sources of BBB-associated apoE), and in these mice crossed with APP/PS1-21 and P301S tau lines, and treated with a cell-signaling activated protein C (APC) analog, 3K3A-APC. The results of this work may lead to new ways of thinking about pathogenesis, treatment and early prevention of cognitive impairment, dementia and AD for which we still do not have effective therapies.

总体 - 项目摘要/摘要 这是一项关于痴呆和遗传风险血管贡献的持续多学科计划 阿尔茨海默氏病的因素，包括多个项目，核心，机构和24位研究人员 Zilkha神经遗传学研究所，史蒂文斯神经影像学研究所，阿尔茨海默氏病研究 南加利福尼亚大学（南加州大学），加利福尼亚州南加州大学（ADRC）中心；华盛顿大学骑士ADRC，部门 华盛顿大学神经病学，密苏里州圣路易斯；亨廷顿医学研究机构，加利福尼亚州帕萨迪纳； 亚利桑那州班纳·阿尔茨海默氏症研究所和梅奥诊所；欧文分校心理学系；分子医学系， Scripps研究所；和临床脑科学中心，大学。苏格兰爱丁堡的。总体 该程序的目标是测试AD的“神经血管假设”，并确定是否神经血流 在早期认知能力下降的发病机理中起着重要作用，因此可能是新的新疗法 治疗早期认知障碍，痴呆和早期AD的目标。该计划包括继续参与 通过本研究计划的各个方面的成熟研究人员。调查人员的集体专业知识， 每个项目的整体环境，初步结果和实验设计和支持核心 在过去的四年中，该计划取得了巨大的成功。在此期间，我们收集了疫苗 数据量，分析它们并撰写了令人印象深刻的高影响力论文。我们的续约是 集中于载脂蛋白E（APOE），这是AD的主要遗传危险因素。我们提出纵向研究 在APOE4载体（ε3/ε4;ε4/ε4）中，AD的遗传风险很高并发展早期脑血管变化 包括相对于APOE3纯合子（ε3/ε3）的血脑屏障（BBB）的分解 AD的风险和发展较慢的脑血管变化。我们预计将遵循402个APOE4载体和465 APOE3纯合子（45-90岁）最初以认知单pair的（Cu，75％）或轻度认知的认知招募 损害（MCI，25％）。这包括在最初的P01期间参加该计划的510名参与者，以及 在续签的前三年将招募360名新参与者。在这些apoe4和apoe3中 参与者我们将应用尖端的分子和成像方法来研究BBB/血管的贡献 临床前认知下降，大脑连通性丧失，神经退行性的功能障碍和纵向临床 与Aβ和TAU AD生物标志物有关 异常（CSF，PET）。在实验上，我们将研究BBB/血管功能障碍与突触和 APOE（敲入）Flox/Flox（KIF）小鼠的神经元功能障碍和行为，并没有APOE删除 星形胶质细胞和周细胞（与BBB相关的APOE的主要来源），在这些小鼠中与App/ps1-21交叉 和p301s tau系，并用细胞信号活化蛋白C（APC）类似物（3K3A-apc）处理。结果 这项工作可能导致有关发病机理，治疗和早期预防认知的新思维方式 我们仍然没有有效疗法的障碍，痴呆和广告。