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.

血管性认知障碍和痴呆 (VCID) 被定义为触发的一种痴呆形式 脑血管受损或脑血管疾病。脑淀粉样血管病（CAA）， 这是淀粉样 ß-蛋白 (Aß) 在主要中小型体内和沿的积累 脑动脉和小动脉以及脑微血管，是常见的脑血管 可能导致老年人出现 VCID 的疾病。毫不奇怪，随着 Aß 的参与，CAA 成为了 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 导致 AD 及相关疾病患者出现痴呆症，人们越来越认识到 后者是认知障碍的潜在驱动因素。然而，脑血管病的原因 淀粉样蛋白的形式及其对下游病理和早期认知障碍的贡献 仍不清楚。 铜稳态的改变被认为是神经退行性疾病的一个重要因素 疾病。早期发现表明铜可能在淀粉样蛋白的形成中发挥重要作用 沉积物以及随后的神经元功能障碍和认知障碍。但相对较少 已知脑血管淀粉样沉积物中铜的积累，这些沉积物是 与早发性 VCID 相关。因此，我们提议的总体假设是铜发挥作用 在 CAA 中驱动纤维状淀粉样蛋白组装的作用以及随后的积累 脑血管淀粉样蛋白沉积物中的铜促进下游病理学和早期 出现认知障碍。为了检验这一假设，我们提出了三个具体目标。第一的， 我们将确定与实质相比，血管淀粉样沉积物是否表现出高水平的铜 AD、散发性 CAA 和家族性 CAA 死后人脑组织样本中的淀粉样斑块 患者和转基因小鼠模型。其次，我们将研究铜对 Aß 原纤维的影响 集会。第三，我们将确定增加或减少铜含量对 Tg-SwDI 小鼠 CAA 的发展、下游病理学和认知障碍。 目前，还没有专门针对 CAA 的有效疗法或可靠的生物标志物。这些 由于我们对装配和独特的结构缺乏了解，缺陷变得更加复杂 脑血管淀粉样蛋白的属性及其导致 CAA 形成和的独特特征 随后的病理。目前的提案重点关注铜在这些事件中的作用，将寻求 填补我们知识中的这一关键空白，并将增进我们对 CAA 发病机制的理解 并提供对新型诊断标记物和潜在治疗方法的开发的见解 CAA 和 VCID 的干预措施。