Cerebral Vascular Smooth Muscle Dysfunction in Alzheimer's Disease

抽象的。 阿尔茨海默病（AD）是一种影响数百万美国人的破坏性神经退行性疾病。尽管 几十年来，人们对记忆和认知缺陷进行了研究，并进行了大量的临床试验， 疾病，AD发生和进展的潜在机制仍不清楚，临床试验的结果 不确定有趣的是，AD的早期事件是脑血流量（CBF）减少， 低聚淀粉样蛋白β（Aβ）的积累和脑血管直径的变化， AD患者和AD动物模型。努力探索血管系统是否有助于AD， 主要集中在内皮功能障碍的机制。然而，如何血管平滑肌（VSM）， 含有调节动脉/小动脉直径和CBF的收缩装置， 导致AD发展和进展的机制知之甚少。本建议的总体目标是 通过全面评估大脑和大脑之间的联系， VSM功能障碍和Aβ蓄积/暴露。我们将讨论新的中心假设，即Aβ 暴露通过改变离子通道的聚集和活性来改变VSM功能和血管反应性 CaV1.2是VSM收缩所必需的。我们进一步假设，一个单一的磷酸化状态， CaV1.2氨基酸- S1928 -介导Aβ依赖性对CaV1.2时空特性的影响这一创新 假设是在强有力的初步数据的基础上制定的，这些数据表明， Aβ暴露对增加S1928磷酸化的影响。这与CaV1.2活性增加相关， Aβ暴露诱导CaV1.2偶联事件。CaV1.2偶联增加导致 钙离子内流放大，导致血管收缩增强和对Aβ反应的CBF改变，因此 强调了这一补充的重要性。除了S1928在控制动脉粥样硬化中不可预见的作用之外， CaV1.2和血管功能对Aβ的反应，一个新兴的和创新的概念是，pS1928是一个主要的 AD的危险因素我们的多尺度现代方法包括创新的显微技术， 将实施复杂的生物化学、电生理学、计算机分析和独特的动物模型 探索以下目标。目的1将检验Aβ暴露增加CaV1.2聚集、活性的假设 和耦合选通。目的2将检验以下假设：pS1928对于Aβ诱导的CaV1.2聚集是必需的， 耦合选通该应用程序的影响在于揭示一个链接的基本新机制见解 脑VSM功能障碍与AD之间的关系，可用于合理开发治疗 降低血管和神经并发症风险的策略。

Abstract . Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions of Americans. Despite decades of research to understand memory and cognitive deficits and numerous clinical trials to treat the disease, mechanisms underlying AD development and progression remain unclear and outcomes of clinical trials uncertain. Intriguingly, an early event in AD is a decrease of cerebral blood flow (CBF) that has been associated with oligomeric amyloid β (Aβ) accumulation and changes in the diameter of cerebral blood vessels in both human with AD and animal models of AD. Efforts to explored whether the vasculature contributes to AD have mainly centered on mechanisms of endothelial dysfunction. However, how vascular smooth muscle (VSM), which contain the contractile apparatus to modulate arterial/arteriole diameter and CBF, are affected by Aβ leading to AD development and progression are poorly understood. The overall objective of this proposal is to address these fundamental knowledge gaps by providing a comprehensive evaluation of a link between cerebral VSM dysfunction and Aβ accumulation/exposure. We will address the novel central hypothesis that Aβ exposure alters VSM function and vascular reactivity by modifying the clustering and activity of the ion channel CaV1.2, which is essential for VSM contraction. We further hypothesize that the phosphorylation state of a single CaV1.2 amino acid - S1928 – mediates Aβ-dependent effects on CaV1.2 spatiotemporal properties. This innovative hypotheses are formulated on the basis of strong preliminary data indicating an unanticipated and remarkable effect of Aβ exposure in increasing S1928 phosphorylation. This was correlated with increased CaV1.2 activity and the induction of coupled CaV1.2 events upon Aβ exposure. Increased CaV1.2 coupling results in a net amplification of Ca2+ influx leading to enhanced vasoconstriction and altered CBF in response to Aβ, thus underscoring the significance of this supplement. Beyond the unforeseen role for S1928 in control of arterial CaV1.2 and vascular function in response to Aβ, an emerging and innovative concept is that pS1928 is a major risk factor in AD. Our multiscale contemporary approach that includes innovative microscopy techniques, sophisticated biochemistry, electrophysiology, in silico analysis and unique animal models will be implemented to explore the following aims. Aim 1 will test the hypothesis that Aβ exposure increases CaV1.2 clustering, activity and coupled gating. Aim 2 will test the hypothesis that pS1928 is essential for Aβ-induced CaV1.2 clustering and coupled gating. The impact of the application lies in uncovering fundamental new mechanistic insight of a link between cerebral VSM dysfunction and AD that could be exploited for the rational development of treatment strategies that reduce the risk of vascular and neuronal complications.