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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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。尽管 几十年来了解记忆和认知缺陷的研究以及治疗这种疾病的大量临床试验 疾病、阿尔茨海默病发生和进展的机制尚不清楚，临床试验的结果 不确定。有趣的是，AD的一个早期事件是脑血流量(CBF)减少，这与 均伴有低聚淀粉样蛋白β(Aβ)积聚和脑血管内径改变 人类阿尔茨海默病和AD动物模型。探索血管系统是否与阿尔茨海默病有关的努力 主要集中在内皮功能障碍的机制上。然而，血管平滑肌(VSM)如何， 其中包含调节动脉/小动脉直径和脑血流量的收缩装置，受Aβ影响 导致阿尔茨海默病的发生和进展的机制还知之甚少。这项提议的总体目标是 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 血管紧张素转换酶功能障碍与β积聚/暴露。我们将解决一个新的中心假设，即Aβ 暴露通过改变离子通道的聚集和活性改变VSM功能和血管反应性 CaV1.2，这是VSM收缩所必需的。我们进一步假设，单个蛋白的磷酸化状态 CaV1.2氨基酸-S1928-介导Aβ依赖对CaV1.2时空特性的影响。这是一项创新 假设是建立在强有力的初步数据的基础上的，这些数据表明 A-β暴露对S1928蛋白磷酸化的影响这与CaV1.2活性增加和 β暴露时CaV1.2耦合事件的诱发。增加CaV1.2耦合导致网络 钙离子内流的放大导致血管收缩增强和脑血流量改变，以响应Aβ，从而 强调本补编的重要性。超越S1928在动脉控制中的不可预见的作用 CaV1.2和血管功能在应对Aβ时，一个新兴和创新的概念是PS1928是一种主要的 AD的危险因素。我们的多尺度当代方法包括创新的显微技术， 将实施先进的生物化学、电生理学、电子分析和独特的动物模型 探索以下目标。目标1将检验这样的假设，即暴露于β会增加CaV1.2的聚集活性 和耦合门控。目标2将检验假设，即pS1928对于β诱导的CaV1.2聚集是必不可少的，并且 联动门控。应用程序的影响在于揭示了对链接的基本新机制洞察 脑VSM功能障碍与阿尔茨海默病的关系 降低血管和神经元并发症风险的策略。

项目成果

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

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.

• DOI: 10.1007/s00018-020-03582-z
• 发表时间: 2021-01
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Nieves-Cintrón M;Flores-Tamez VA;Le T;Baudel MM;Navedo MF
• 通讯作者: Navedo MF

Transfer of nuclear and ribosomal material from Sox10-lineage cells to neurons in the mouse brain.

• DOI: 10.1084/jem.20221632
• 发表时间: 2023-07-03
• 期刊: The Journal of experimental medicine