Cerebrovascular endothelial cilia in the pathogenesis and therapy of Alzheimer's disease

脑血管内皮纤毛在阿尔茨海默病发病机制和治疗中的作用

基本信息

批准号：
10575082
负责人：
Wissam Aboualaiwi
金额：
$ 14.91万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10575082
关键词：
Acetylcholine Affect Age Months Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy Amyloid beta-Protein Anabolism Animal Model Attenuated Biology Blood Vessels Brain Cardiovascular system Cell model Cerebral Amyloid Angiopathy Cerebrovascular Disorders Cerebrovascular system Cerebrum Cilia Cilium Microtubule Cognition Cognitive Cues Data Deposition Development Disease Disease Progression Endothelium Environment Functional disorder Genetic Diseases Goals Histologic Human Hypertension Impaired cognition Impairment Incidence Intuition Investigation Knockout Mice Knowledge Learning Length Link Liquid substance Mechanical Stress Mechanics Mediating Memory Memory impairment Microcirculation Modeling Molecular Mus Muscarinic Acetylcholine Receptor Neurons Nitric Oxide Nitric Oxide Pathway Organelles Outcome Pathogenesis Pathway interactions Patients Persons Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Physiological Play Process Production Receptor Activation Receptor Signaling Research Risk Role Sampling Sensory Signal Pathway Signal Transduction Structure Surface Symptoms System Testing Vascular Cognitive Impairment Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vascular blood supply abeta accumulation abeta deposition aged amyloid pathology blood pressure regulation brain endothelial cell cerebral artery cerebrovascular cholinergic ciliopathy cilium biogenesis cognitive function defined contribution design environmental change extracellular hypertension treatment in vivo molecular targeted therapies mouse model mutant neuroinflammation neuroprotection neurovascular injury neurovascular unit new therapeutic target novel pharmacologic prevent receptor response shear stress therapeutic target therapy design transcriptional reprogramming translational impact transmission process vascular factor

项目摘要

Primary cilia are microtubule-based organelles, extending from the surface of vascular endothelial cells to sense extracellular signaling cues and fluid-shear stress. Cilia dysfunctions (ciliopathies) have been linked to numerous genetic disorders, and manifest a broad range of symptoms, including hypertension (HTN) and cognitive and memory dysfunction. We demonstrated that the inability of primary endothelial cilia to sense and transmit fluid shear stress can lead to nitric oxide (NO) deficiency and cause vascular HTN. HTN can cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment, contributing to the progression of Alzheimer’s disease (AD). In addition, decreased biosynthesis of NO contributes to CAA in AD patients through increased deposition of beta amyloid (Aβ). However, the molecular mechanisms underlying the pathogenesis of HTN and AD are incompletely understood thereby limiting our ability to prevent initiation and progression of this disease. Recent studies have identified specific mAChR- regulated pathways as novel therapeutic targets for AD. Muscarinic acetylcholine receptors (mAChRs) are also expressed throughout the cardiovascular system and can regulate BP and NO biosynthesis. However, the connection between cilia, mAChR signaling, and HTN in the pathogenesis of AD has never been investigated before. Supported primarily by our recent discovery of the AChM3R localization to primary cilia, we propose a bold idea to look at the pathophysiological roles of cerebrovascular ciliary receptors in BP and in AD in vivo. This application is designed to advance the concept that in early stages of AD, diminished cilia- mediated NO biosynthesis and deposition of endothelium-derived Aβ in cerebral blood vessel wall is an important mechanism contributing to pathogenesis HTN and AD. We generated vascular-specific AChM3R and Tg737 KO mice, in which AChM3R and Tg737 (important for ciliogenesis) were specifically deleted from the vascular endothelia. Interestingly, these mice developed high BP, associated with attenuated NO production, and altered cognitive function. These studies demonstrated the physiological significance of primary cilia-derived NO in the long-term control of vascular and cognitive function. In this proposal, we formulated the hypothesis that endothelial ciliary AChM3R contributes to AD progression through diminished NO biosynthesis. In Aim 1, we will study the effect of AChM3R or cilia deletion from vascular endothelia in 3xTgAD model on Aß accumulation, vascular reactivity, and brain vascular integrity/function. We will also test the effect of novel pharmacological modulators on enhancing ciliary AChM3R-mediated NO biosynthesis. In Aim 2, we will examine the role of cerebrovascular cilia and AChM3R KO in BP and AD manifestations in the 3xTgAD model. We anticipate that successful completion of this project will offer new opportunities to utilize endothelial mAChRs as molecular targets for therapeutic interventions designed to prevent detrimental effects of HTN on cerebrovascular and cognitive function.

原发性纤毛是基于微管的细胞器，从血管内皮细胞的表面延伸至细胞外信号提示和流体剪切应力。纤毛功能障碍（纤毛病）已与许多遗传疾病，表现出广泛的症状，包括高血压（HTN）和认知和认知和内存功能障碍。我们证明了原发性内皮纤毛无力感知和传输流体剪切应力会导致一氧化氮（NO）缺乏并引起血管HTN。 HTN会导致脑微血管内皮机械应力，损害神经血管单元，并最终诱导认知障碍，促进阿尔茨海默氏病（AD）的进展。另外，NO的生物合成降低通过增加β-淀粉样蛋白（Aβ）的沉积来促进AD患者的CAA。但是，分子 HTN和AD发病机理的基础机制未完全理解，从而限制了我们的防止这种疾病的开始和进展的能力。最近的研究已经确定了特定的MACHR- 调节途径是AD的新型治疗靶标。毒蕈碱乙酰胆碱受体（MACHR）也是在整个心血管系统中表达，可以调节BP并且无生物合成。但是， AD发病机理中纤毛，MACHR信号传导和HTN之间的联系从未被研究前。在我们最近发现ACHM3R本地化到主要纤毛的基础上，我们提出了一个大胆的想法看脑血管睫状受体在BP和在AD In Vivo中。该应用程序旨在推动以下概念，即在AD的早期阶段减少了纤毛。介导的无生物合成和内皮衍生的Aβ在脑血管壁中的沉积是有助于发病机理HTN和AD的重要机制。我们产生了血管特异性的ACHM3R和 TG737 KO小鼠，其中ACHM3R和TG737（对于纤毛生成很重要）是从从血管内皮。有趣的是，这些小鼠发育高BP，与无生产减弱有关，并且改变认知功能。这些研究证明了原发性纤毛的物理意义长期控制血管和认知功能的否。在此提案中，我们提出了假设该内皮睫状ACHM3R通过降低的无生物合成有助于AD进展。目标 1，我们将研究3xTGAD模型中血管内皮中Achm3R或纤毛缺失的影响积累，血管反应性和脑血管完整性/功能。我们还将测试新颖的效果药理学调节剂可增强睫状ACHM3R介导的无生物合成。在AIM 2中，我们将检查脑血管纤毛和ACHM3R KO在BP中的作用以及在3xTGAD模型中的AD表现。我们预计该项目的成功完成将为利用内皮提供新的机会 MACHR作为治疗干预措施的分子靶标，旨在防止HTN对脑血管和认知功能。