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

总体-项目总结/摘要 这是一个关于血管对痴呆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24名研究人员从 Zilkha神经遗传学研究所，史蒂文斯神经成像和信息学研究所，阿尔茨海默病研究 中心（ADRC），南加州大学（USC），洛杉矶，加利福尼亚州;华盛顿大学奈特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，帕萨迪纳，加利福尼亚州; 班纳阿尔茨海默氏症研究所和马约诊所，亚利桑那州;心理学，UC Irvine; Dept.分子医学， 斯克里普斯研究所和苏格兰爱丁堡大学临床脑科学中心。整体 该计划的目标是测试AD的“神经血管假说”，并确定神经血管是否 在早期认知能力下降的发病机制中起主要作用，因此可能是一种关键的新治疗方法。 以治疗早期认知障碍、痴呆和早期AD为目标。该计划包括继续参与 在本研究计划的各个方面都有出色的研究人员。调查人员的集体专业知识， 每个项目的总体环境、初步结果和实验设计以及支持核心 在过去的四年里，这个项目取得了巨大的成功。在此期间，我们收集了大量 他收集了大量的数据，进行了分析，并撰写了大量具有高度影响力的论文。我们的更新是 主要集中在载脂蛋白E（APOE），AD的主要遗传风险因素。我们建议进行纵向研究 在AD遗传风险高且发生早期脑血管变化的APOE 4携带者（ε3/ε4; ε4/ε4）中 包括血脑屏障（BBB）相对于APOE 3纯合子（ε3/ε3）的破坏， AD的风险和发展缓慢的脑血管变化。我们预计将有402架APOE 4运载工具和465架 APOE 3纯合子（年龄45-90岁）最初入选为认知未受损（CU，75%）或轻度认知功能受损（CU，75%）。 损害（MCI，25%）。这包括510名参与者在最初的P01期间参加了该计划， 在续约的前3年，将招募360名新参与者。在这些APOE 4和APOE 3中， 我们将应用尖端的分子和成像方法来研究BBB/血管的贡献， 临床前认知功能减退、脑连接丧失、神经变性和纵向临床 与Aβ和tau AD生物标志物相关的从CU到MCI和MCI到痴呆的连续体沿着进展 异常（CSF、PET）。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 APOE（敲入）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apoE的关键来源），并在这些小鼠与APP/PS1-21杂交 和P301 S tau系，并用细胞信号传导活化蛋白C（APC）类似物3 K3 A-APC处理。结果 这项工作可能会导致新的思维方式的发病机制，治疗和早期预防认知 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.