The Role of Copper in Cerebral Amyloid Angiopathy

铜在脑淀粉样血管病中的作用

• 批准号: 9305169
• 负责人: LISA M MILLER
• 金额: --
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2017-05-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305169
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Arteries; Automobile Driving; Binding; Blood Vessels; Brain; Brain Diseases; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Comorbidity; Comparative Study; Copper; Dementia; Deposition; Development; Disease; Elderly; Event; Exhibits; Familial Cerebral Amyloid Angiopathy; Fluorescence Microscopy; Homeostasis; Human; Impaired cognition; In Vitro; Ions; Knowledge; Laboratories; Lead; Light; Link; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Oxygen; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Play; Proteins; Reactive Oxygen Species; Reporting; Research; Resolution; Roentgen Rays; Role; Senile Plaques; Source; Spectrum Analysis; Sporadic Cerebral Amyloid Angiopathy; Structure; Synchrotrons; Testing; Therapeutic Intervention; Tissue Sample; Transgenic Mice; Vascular Cognitive Impairment; Work; abeta accumulation; absorption; amyloid formation; amyloid pathology; arteriole; brain tissue; cerebral microvasculature; cerebrovascular; cerebrovascular amyloid; diagnostic biomarker; early onset; effective therapy; experimental study; insight; microvascular amyloid; mouse model; novel diagnostics; specific biomarkers

Vascular cognitive impairment & dementia (VCID) is defined as a form of dementia that is triggered by damage to cerebral blood vessels or cerebrovascular disease. Cerebral amyloid angiopathy (CAA), which is accumulation of amyloid ß-protein (Aß) within and along primarily small and medium-sized arteries and arterioles of the brain and in the cerebral microvasculature, is a common cerebral vascular condition that can cause VCID in the elderly. Not surprisingly, with the involvement of Aß, CAA is the most common vascular comorbidity found in the brains of Alzheimer's disease (AD) patients. Although there is evidence that both parenchymal plaque amyloid and cerebral microvascular amyloid can contribute to dementia in patients with AD and related disorders, there is growing recognition that the latter is a potent driver of cognitive impairment. Yet, the reasons as to why cerebral vascular amyloid forms and its contribution to downstream pathologies and early cognitive impairment remain unclear. Altered copper homeostasis has been considered an important factor in the neurodegenerative diseases. Earlier findings suggest that copper may play an important role in the formation of amyloid deposits and in subsequent neuronal dysfunction and cognitive impairment. However, relatively little is known about the accumulation of copper in cerebral vascular amyloid deposits, which are associated with early-onset VCID. Thus, the overall hypothesis of our proposal is that copper plays a role in driving fibrillar amyloid assembly in CAA and that the subsequent accumulation of copper in the cerebrovascular amyloid deposits promotes downstream pathologies and early- onset cognitive impairment. In order to test this hypothesis we propose to three specific aims. First, we will determine if vascular amyloid deposits exhibit high levels of copper compared to parenchymal amyloid plaques in post mortem human brain tissue samples of AD, sporadic CAA and familial CAA patients and in transgenic mouse models. Second, we will investigate the effects of copper on Aß fibril assembly. Third, we will determine the effects of increasing or reducing copper levels on the development of CAA, downstream pathologies and cognitive impairment in Tg-SwDI mice. Currently, there are no effective therapies or reliable biomarkers specifically for CAA. These deficiencies are complicated by our lack of understanding of the assembly and unique structural attributes of cerebral vascular amyloid and their distinctive features that lead to CAA formation and subsequent pathologies. The present proposal, focused on the role of copper in these events, will seek to fill this critical void in our knowledge and will advance our understanding of the pathogenesis of CAA and provide insight into the development of novel diagnostic markers and potential therapeutic interventions for CAA and VCID.

血管认知障碍和痴呆（VCID）被定义为触发的痴呆形式 通过损害脑血管或脑血管疾病。脑淀粉样血管病（CAA）， 这是淀粉样β-蛋白质（Aß）的积累 大脑的动脉和小动脉以及脑微脉管系统是一种常见的脑血管 可能导致VCID的状况。毫不奇怪，随着Aß的参与，CAA是 在阿尔茨海默氏病（AD）患者的大脑中发现的最常见的血管合并症。虽然 有证据表明，副斑块淀粉样蛋白和脑微血管淀粉样蛋白可以 在AD和相关疾病患者中有助于痴呆，越来越认识到 后者是认知障碍的潜在驱动力。但是，为什么脑血管的原因 淀粉样形式及其对下游病理和早期认知障碍的贡献 保持不清楚。 改变的铜稳态被认为是神经退行性的重要因素 疾病。较早的发现表明铜可能在淀粉样蛋白的形成中起重要作用 沉积物以及随后的神经元功能障碍和认知障碍。但是，相对较少 知道铜在脑血管淀粉样蛋白沉积物中的积累 与早发VCID相关。那就是我们提议的总体假设是铜的发挥 在CAA中驱动原纤维淀粉样蛋白组件中的作用，随后的积累 脑血管淀粉样蛋白沉积物中的铜促进了下游病理和早期 发作认知障碍。为了检验这一假设，我们提出了三个特定目标。第一的， 我们将确定与实质相比，血管淀粉样蛋白沉积是否表现出高水平的铜 验尸后的AD，零星CAA和家族CAA的淀粉样菌斑样品 患者和转基因小鼠模型。其次，我们将研究铜对Aß纤维的影响 集会。第三，我们将确定提高或降低铜水平对铜的影响 TG-SWDI小鼠的CAA，下游病理和认知障碍的发展。 目前，没有专门针对CAA的有效疗法或可靠的生物标志物。这些 由于我们对集会和独特的结构缺乏理解，缺陷使缺陷变得复杂 大脑血管淀粉样蛋白的属性及其独特的特征，导致CAA形成和 随后的病理。目前的提议侧重于铜在这些事件中的作用，将寻求 在我们的知识中填补这一关键空隙，并将提高我们对CAA发病机理的理解 并洞悉新型诊断标记和潜在疗法的发展 CAA和VCID的干预措施。