CEREBRAL AMYLOID ANGIOPATHY AND MECHANISMS OF BRAIN AMYLOID ACCUMULATION

脑淀粉样蛋白血管病和脑淀粉样蛋白积累的机制

基本信息

批准号：
9884824
负责人：
Brian J Bacskai
金额：
$ 113.43万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884824
关键词：
Abeta clearance Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Amyloid deposition Animals Autopsy Biological Blood Circulation Blood Preservation Blood Vessels Brain Brain Injuries Carbon Dioxide Cerebral Amyloid Angiopathy Cerebrovascular Disorders Cerebrovascular Physiology Cerebrovascular Trauma Cerebrovascular system Cerebrum Clinical Collaborations Deposition Diagnosis Disease Disease Progression Disease model Endothelium Foundations Functional Magnetic Resonance Imaging Functional disorder Gene Expression Goals Human Image Impairment Individual Injury International Interruption Intervention Trial Investigation Lead Leadership Lesion Ligands Link Magnetic Resonance Imaging Methodology Molecular Molecular Analysis Non-Invasive Cancer Detection Pathogenicity Pathology Pharmacology Physiological Physiology Pittsburgh Compound-B Play Process Pulse Pressure Research Priority Role Severities Smooth Muscle Smooth Muscle Myocytes Stimulus Structure Tissues Transgenic Mice Translating Vascular Cognitive Impairment Vascular Diseases Vascular Endothelium Wild Type Mouse abeta accumulation abeta deposition age related aging population amyloid peptide blood pressure reduction brain pathway cerebrovascular design experimental study gene product human subject imaging modality laser capture microdissection mouse model multidisciplinary multiphoton microscopy novel optical imaging prevent public health relevance serial imaging temporal measurement vascular injury

项目摘要

DESCRIPTION (provided by applicant): The small vessels of the brain play key roles in both age-related vascular cognitive impairment and clearance of the ß-amyloid peptide (Aß). Cerebrovascular deposition of Aß as cerebral amyloid angiopathy (CAA) sets up a potentially self-reinforcing mechanistic loop in which CAA-related vascular injury and dysfunction lead to reduced Aß clearance and progressively worse Aß deposition, CAA, and Alzheimer disease pathology. We propose a systematic, multidisciplinary analysis of the mechanisms underlying Aß-related cerebrovascular injury, vascular dysfunction, and impaired perivascular clearance in human CAA and transgenic mouse models. Specific experiments, each designed to translate from mouse models to reliably diagnosed human CAA, focus on the effects of CAA on cerebral small vessel compliance, physiologic reactivity, and their relationship to focal brain lesions (SA1), the effects of altered physiology on Aß clearance and accumulation (SA2), and the effects of CAA on gene expression in cerebrovascular endothelium and smooth muscle (SA3). The proposal builds on the applicants' long record of successful mutual collaborations and their internationally recognized expertise and leadership in noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of cerebrovascular gene expression in control and disease states. The proposal also builds on a wide range of cutting-edge methodologic advances such as ultrahigh-field functional MRI, serial molecular Aß imaging, intravital multiphoton microscopy, vasculomic analysis, and laser-capture microdissection of post-mortem tissue. Successful completion of the proposed highly translational experiments will determine Aß's vascular effects at the molecular, single-vessel, and whole-brain levels, establish their relevance to clinical disease, and yield entirely new and promising approaches to interrupting the vicious cycle of vascular injury and reduced Aß clearance key to the propagation of CAA and Alzheimer's disease.

描述（由申请人提供）：大脑小血管在与年龄相关的血管性认知障碍和 β-淀粉样肽 (Aß) 的清除中发挥着关键作用。潜在的自我强化机制循环，其中 CAA 相关的血管损伤和功能障碍导致 Aß 清除率降低和 Aß 沉积逐渐恶化、CAA 和阿尔茨海默病我们提出对人类 CAA 和转基因小鼠模型中 Aß 相关脑血管损伤、血管功能障碍和血管周围清除受损的机制进行系统的、多学科的分析，每个实验都旨在从小鼠模型转化为可靠诊断的人类 CAA。重点关注 CAA 对脑小血管顺应性、生理反应性及其与局灶性脑损伤 (SA1) 的关系的影响，生理学改变对 Aß 清除和积累 (SA2) 的影响，以及关于脑血管内皮和平滑肌 (SA3) 基因表达的 CAA 该提案建立在申请人长期成功的相互合作记录以及他们在人体 CAA 无创检测和分析、血管结构实时测量方面的国际公认的专业知识和领导地位的基础上。该提案还建立在一系列尖端方法学进展的基础上，例如超高场功能 MRI、系列技术。分子 Aß 成像、活体多光子显微镜、血管分析和死后组织的激光捕获显微切割成功完成拟议的高度转化实验将确定 Aß 在分子、单血管和全脑水平上的血管效应，建立。其与临床疾病的相关性，并完全产生新的、有前途的方法来中断血管损伤的恶性循环和减少 Aß 清除率，而 Aß 清除率是 CAA 和阿尔茨海默病传播的关键。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cerebral amyloid angiopathy and Alzheimer disease - one peptide, two pathways.

脑淀粉样血管病和阿尔茨海默病 - 一种肽，两种途径。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Greenberg, Steven M;Bacskai, Brian J;Hernandez;Pruzin, Jeremy;Sperling, Reisa;van Veluw, Susanne J
通讯作者：
van Veluw, Susanne J

Blood-Brain Barrier Leakage and Microvascular Lesions in Cerebral Amyloid Angiopathy.

脑淀粉样血管病中的血脑屏障渗漏和微血管病变。

DOI：
发表时间：
2019-02
期刊：
影响因子：
8.3
作者：
Freeze, Whitney M;Bacskai, Brian J;Frosch, Matthew P;Jacobs, Heidi I L;Backes, Walter H;Greenberg, Steven M;van Veluw, Susanne J
通讯作者：
van Veluw, Susanne J