The Role of Copper in Cerebral Amyloid Angiopathy

铜在脑淀粉样血管病中的作用

• 批准号: 9173698
• 负责人: LISA M MILLER
• 金额: $ 39.5万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173698
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Arteries; Automobile Driving; Binding; Biological Markers; Blood Vessels; Brain; 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; 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; absorption; amyloid formation; amyloid pathology; arteriole; brain tissue; cerebral microvasculature; cerebrovascular; cerebrovascular amyloid; copper-binding protein; diagnostic biomarker; early onset; effective therapy; insight; microvascular amyloid; mouse model; novel diagnostics; research study

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.

血管性认知障碍和痴呆（VCID）被定义为一种形式的痴呆， 脑血管损伤或脑血管疾病。脑淀粉样血管病（CAA）， 其是淀粉样β-蛋白（AAPs）在主要是小和中等大小的内和沿着的积累， 脑的动脉和小动脉以及脑微血管系统中，是常见的脑血管 可能导致老年人VCID的情况。毫不奇怪，有了Awesome的参与，CAA是 阿尔茨海默病（AD）患者大脑中最常见的血管合并症。虽然 有证据表明实质斑块淀粉样蛋白和脑微血管淀粉样蛋白都可以 在AD和相关疾病患者中，人们越来越认识到， 后者是认知障碍的有力驱动因素。然而，脑血管疾病的原因 淀粉样蛋白形式及其对下游病理和早期认知障碍的作用 仍然不清楚。 铜稳态的改变被认为是神经退行性变的重要因素。 疾病早期研究结果表明铜可能在淀粉样蛋白的形成中发挥重要作用 沉积和随后的神经元功能障碍和认知障碍。然而，相对较少 已知铜在脑血管淀粉样沉积物中的积累， 与早发性VCID有关因此，我们的建议的总体假设是，铜扮演 在CAA中驱动纤维状淀粉样蛋白组装的作用， 脑血管淀粉样沉积物中的铜促进下游病理和早期- 发作性认知障碍为了验证这一假设，我们提出了三个具体目标。第一、 我们将确定血管淀粉样蛋白沉积物是否比实质组织表现出高水平的铜， AD、散发性CAA和家族性CAA尸检人脑组织样本中的淀粉样蛋白斑块 患者和转基因小鼠模型。其次，我们将研究铜对紫茎泽兰原纤维的影响 组装件.第三，我们将确定增加或减少铜水平对 Tg-SwDI小鼠中CAA、下游病理学和认知障碍的发展。 目前，还没有针对CAA的有效治疗方法或可靠的生物标志物。这些 由于我们对装配和独特的结构缺乏了解， 脑血管淀粉样蛋白的属性及其导致CAA形成的独特特征， 后续病理本提案重点关注铜在这些事件中的作用，将寻求 填补了我们知识中的这一关键空白，并将促进我们对CAA发病机制的理解 并为开发新的诊断标志物和潜在的治疗方法提供了见解。 CAA和VCID的干预措施。