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

• 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
• 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' s Disease; Alzheimer' 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

 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）：脑小血管在年龄相关的血管性认知障碍和β-淀粉样肽（AAP 12）清除中起关键作用。脑淀粉样血管病（CAA）的脑血管沉积建立了一个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AAR清除率降低，AAR沉积、CAA和阿尔茨海默病病理学逐渐恶化。我们提出了一个系统的，多学科的分析机制，在人类CAA和转基因小鼠模型中，与血管相关的脑血管损伤，血管功能障碍和血管周围清除受损。具体的实验，每个设计从小鼠模型转化为可靠诊断的人CAA，重点是CAA对脑小血管顺应性，生理反应性的影响，以及它们与局灶性脑病变的关系（SA 1），生理学改变对Ablastin清除和积累的影响（SA 2），以及CAA对脑血管内皮和平滑肌中基因表达的影响（SA 3）。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类CAA的非侵入性检测和分析、活转基因小鼠模型中血管结构和生理学的实时测量以及对照和疾病状态下脑血管基因表达的分子分析方面的国际公认的专业知识和领导地位的基础上。该提案还建立在广泛的前沿方法学进展的基础上，如超高场功能性MRI，系列分子血管成像，活体多光子显微镜，血管组学分析和死后组织的激光捕获显微切割。成功完成所提出的高度转化的实验将确定在分子、单血管和全脑水平上的Ablast的血管效应，建立它们与临床疾病的相关性，并产生全新的和有前途的方法来中断血管损伤的恶性循环和减少Ablast清除，这是CAA和阿尔茨海默病传播的关键。