The Role of Copper in Cerebral Amyloid Angiopathy

血管性认知障碍和痴呆(VCID)被定义为一种被触发的痴呆 脑血管受损或脑血管疾病。脑淀粉样血管病(CAA)， 这是淀粉样蛋白(Aü)在中小型企业内部和沿线的积累 动脉和小动脉位于大脑的微血管系统中，是一种常见的脑血管 可导致老年人发生VCID的情况。毫不奇怪，在阿伯的参与下，CAA是 阿尔茨海默病(AD)患者大脑中最常见的血管共病。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 阿尔茨海默病患者的痴呆症和相关疾病，人们越来越认识到 后者是认知障碍的一个强有力的驱动因素。然而，为什么脑血管 淀粉样蛋白的形态及其在下游病变和早期认知功能障碍中的作用 目前仍不清楚。 铜稳态改变被认为是神经退行性变的一个重要因素 疾病。早期的发现表明，铜可能在淀粉样蛋白的形成中起重要作用。 沉积以及随后的神经元功能障碍和认知功能障碍。然而，相对较少的 已知的是铜在脑血管淀粉样沉积中的积累，这是 与早发性VCID有关。因此，我们提议的总体假设是铜起作用 在CAA中驱动纤维淀粉样蛋白组装的作用以及随后积累的 脑血管淀粉样蛋白沉积中的铜促进下游病理和早期- 发作性认知障碍。为了检验这一假设，我们提出了三个具体目标。第一, 我们将确定血管淀粉样蛋白沉积与实质相比是否显示出高水平的铜。 AD、散发性CAA和家族性CAA尸检标本中的淀粉样斑块 在患者和转基因小鼠模型中。第二，我们将研究铜对A？原纤维的影响 集合。第三，我们将确定提高或降低铜水平对环境的影响 TG-Swdi小鼠CAA的发生、下游病变和认知功能障碍。 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，缺陷变得更加复杂 脑血管淀粉样蛋白的属性及其与CAA形成和预后的关系 随后的病理改变。目前的提案侧重于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 为开发新的诊断标记物和潜在的治疗方法提供了洞察力 对CAA和VCID的干预。

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.