Cerebral Vascular Smooth Muscle Dysfunction in Alzheimer's Disease

阿尔茨海默氏病的脑血管平滑肌功能障碍

基本信息

批准号：
10488479
负责人：
Manuel F Navedo
金额：
$ 39.79万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10488479
关键词：
Acute Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology American Amino Acids Amyloid beta-Protein Angiotensin II Animal Model Arteries Biochemistry Blood Vessels Blood capillaries Brain Caliber Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Chemosensitization Clinical Clinical Trials Cognitive deficits Coupled Coupling Data Development Disease Electrophysiology (science)Endothelial Cells Evaluation Event Functional disorder Goals Grant Human Hypertension Impaired cognition Impairment Ion Channel Knowledge Link Measurement Mediating Memory Loss Memory impairment Microscopy Mission Modeling Muscle Contraction Muscle function Neurodegenerative Disorders Neurons Nutrient Optics Outcome Oxygen Pathologic Pathway interactions Patients Phosphorylation Phosphorylation Site Physiological Productivity Property Proteins Public Health Regulation Research Risk Risk Factors Role Signal Transduction Site Synapses Techniques Testing Therapeutic United States National Institutes of Health Vascular Smooth Muscle Work abeta accumulation arteriole base cerebrovascular endothelial dysfunction experimental study health goals hyperphosphorylated tau in silico in vivo innovation insight nano novel novel therapeutic intervention oAβ parent grant patch clamp response spatiotemporal targeted therapy trials therapy development tool treatment strategy vasoconstriction voltage

项目摘要

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.

抽象的。阿尔茨海默病（AD）是一种毁灭性的神经退行性疾病，影响着数百万美国人。数十年的研究旨在了解记忆和认知缺陷，并进行了大量的临床试验来治疗疾病、AD 发生和进展的机制和临床试验的结果仍不清楚有趣的是，AD 的早期事件是与之相关的脑血流量 (CBF) 减少。低聚淀粉样蛋白 β (Aβ) 积累以及脑血管直径的变化患有 AD 的人类和 AD 动物模型已努力探索脉管系统是否会导致 AD。主要集中于内皮功能障碍的机制，然而，血管平滑肌（VSM）如何，含有调节动脉/小动脉直径和 CBF 的收缩装置，受 Aβ 影响对 AD 发展和进展的了解甚少。该提案的总体目标是通过对大脑之间的联系进行全面评估来解决这些基本知识差距 VSM 功能障碍和 Aβ 积累/暴露我们将讨论 Aβ 的新中心假设。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，这是VSM收缩所必需的，我们进一步追踪了单个磷酸化状态。 CaV1.2 氨基酸 - S1928 - 介导 Aβ 依赖性对 CaV1.2 时空特性的影响。假设是在强有力的初步数据的基础上提出的，这些数据表明了意想不到的和显着的 Aβ 暴露对增加 S1928 磷酸化的影响这与增加的 CaV1.2 活性和 Aβ 暴露后 CaV1.2 耦合事件的诱导增加导致净值增加。 Ca2+ 流入的放大导致血管收缩增强并改变 CBF 以响应 Aβ，因此强调了 S1928 在控制动脉方面发挥的不可预见的作用。 CaV1.2 和 Aβ 反应的血管功能，一个新兴的创新概念是 pS1928 是一个主要的 AD 的风险因素。我们的多尺度当代方法，包括创新的显微镜技术，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：目标 1 将检验 Aβ 暴露增加 CaV1.2 聚集和活性的假设。耦合门控目标 2 将检验 pS1928 对于 Aβ 诱导的 CaV1.2 聚类至关重要的假设。该应用程序的影响在于揭示了链接的基本新机制。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。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas.

DOI：
10.1038/s42003-022-04398-2
发表时间：
2023-01-03
期刊：
Communications biology
影响因子：
5.9
作者：
通讯作者：

Maladaptive response of arterial myocytes to chronic exposure to Ca2+ channel blockers.

动脉肌细胞对长期暴露于 Ca2 通道阻滞剂的适应不良反应。

DOI：
10.1073/pnas.2011909117
发表时间：
2020
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
O'Dwyer,SamanthaC;Navedo,ManuelF;Santana,LF
通讯作者：
Santana,LF

Deciphering cellular signals in adult mouse sinoatrial node cells.

DOI：
10.1016/j.isci.2021.103693
发表时间：
2022-01-21
期刊：
iScience
影响因子：
5.8
作者：
Reddy GR;Ren L;Thai PN;Caldwell JL;Zaccolo M;Bossuyt J;Ripplinger CM;Xiang YK;Nieves-Cintrón M;Chiamvimonvat N;Navedo MF
通讯作者：
Navedo MF

Cellular and molecular effects of hyperglycemia on ion channels in vascular smooth muscle.