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

总体--项目摘要/摘要 这是一个关于血管对痴呆症和遗传风险的贡献的持续的多学科计划。 阿尔茨海默病的因素与多个项目、核心、机构和来自 Zilkha神经发生研究所，Stevens神经成像和信息学研究所，阿尔茨海默病研究 加州洛杉矶南加州大学(USC)ADRC中心(ADRC)；华盛顿大学骑士ADRC系的 神经病学，华盛顿大学，圣路易斯，密苏里州；亨廷顿医学研究所，加利福尼亚州帕萨迪纳； 阿尔茨海默氏症研究所和梅奥诊所，亚利桑那州；加州大学欧文分校心理学系；分子医学部， 斯克里普斯研究所和临床脑科学中心，大学。苏格兰爱丁堡。整体而言 该项目的目标是检验阿尔茨海默病的神经血管假说，并确定神经血管系统是否 在早期认知功能减退的发病机制中起主要作用，因此可能是一种关键的新疗法 目标是治疗早期认知障碍、痴呆和早期阿尔茨海默病。该计划包括继续参与 在这项研究计划的各个方面都有经验丰富的调查人员。调查人员的集体专业知识， 每个项目和支持核心的总体环境、初步结果和实验设计 在过去的4年里，这个项目取得了相当大的成功。在此期间，我们收集了大量 收集了大量的数据，进行了分析，并撰写了数量惊人的高影响力论文。我们的更新是 主要集中在载脂蛋白E(APOE)，AD的主要遗传危险因素。我们建议进行纵向研究 载脂蛋白4携带者(ε3/ε4；ε4/ε4)具有AD的高遗传风险并发生早期脑血管变化 包括相对于处于较低水平的载脂蛋白3纯合子(ε3/ε3)的血脑屏障的破坏 患阿尔茨海默病的风险较大，脑血管变化较慢。我们预计将有402家APOE4运营商和465家运营商 APOE3纯合子(年龄45-90岁)最初登记为认知正常(CU，75%)或有轻度认知障碍 损害(MCI，25%)。这包括在最初的P01期间登记参加该计划的510名参与者，以及 360名新参与者将在续展的头3年内招聘。在这些APOE4和APOE3中 参与者我们将应用前沿的分子和成像方法来研究血脑屏障/血管的贡献 功能障碍导致临床前认知功能下降、脑连接丧失、神经变性和纵向临床 β和tau AD生物标记物在从慢性充血性心力衰竭到轻度认知功能障碍到痴呆的发展过程中的作用 异常(脑脊液、正电子发射计算机断层扫描)。在实验上，我们将研究血脑屏障/血管功能障碍如何与突触和 载脂蛋白E缺失和不缺失的APOE FLOX/FLOX(KIF)小鼠的神经元功能障碍和行为 星形胶质细胞和周细胞(BBB相关载脂蛋白E的主要来源)，并在这些小鼠中与APP/PS1-21杂交 和P301S tau细胞，并用细胞信号激活蛋白C(APC)类似物3K3A-APC处理。结果是 这项工作可能为认知障碍的发病机制、治疗和早期预防提供新的思路 损害、痴呆症和AD，我们仍然没有有效的治疗方法。

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.