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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.

初级纤毛是以微管为基础的细胞器，从血管内皮细胞表面延伸，细胞外信号线索和流体剪切应力。纤毛功能障碍（纤毛病）与许多遗传性疾病，并表现出广泛的症状，包括高血压（HTN）和认知和记忆障碍我们证明了初级内皮纤毛不能感知和传输液体，剪切应力可导致一氧化氮（NO）缺乏并引起血管HTN。HTN可导致脑微血管内皮机械应力，损伤神经血管单元，并最终诱导认知障碍，导致阿尔茨海默病（AD）的进展。此外，NO的生物合成减少，通过增加β淀粉样蛋白（Aβ）沉积而导致AD患者CAA。然而，分子 HTN和AD的发病机制尚不完全清楚，因此限制了我们的研究。预防这种疾病的发生和发展。最近的研究已经确定了特定的mAChR- 调节途径作为AD的新治疗靶点。毒蕈碱型乙酰胆碱受体（mAChR）也是在整个心血管系统中表达，并且可以调节BP和NO的生物合成。但纤毛、mAChR信号和HTN在AD发病机制中的联系从未被研究过以前我们最近发现AChM 3R定位于初级纤毛，这主要支持了我们的研究，我们提出了一个新的方法。一个大胆的想法，看看脑血管纤毛受体在BP和 in AD in vivo体内.该应用程序旨在推进这一概念，即在AD的早期阶段，纤毛减少- 介导的NO生物合成和内皮源性Aβ在脑血管壁的沉积是一个重要的机制。 HTN和AD发病机制的重要作用。我们产生了血管特异性AChM 3R， Tg 737 KO小鼠，其中AChM 3R和Tg 737（对纤毛发生重要）从小鼠的细胞中特异性缺失。血管内皮有趣的是，这些小鼠出现了高血压，与减弱的NO产生有关，认知功能改变这些研究证明了初级纤毛衍生的生理意义， NO长期控制血管和认知功能。在这个提议中，我们提出了一个假设，内皮纤毛AChM 3R通过减少NO生物合成促进AD进展。在Aim中 1、我们将在3xTgAD模型中研究血管内皮细胞AChM 3R或纤毛缺失对AChM 3R的影响。累积、血管反应性和脑血管完整性/功能。我们还将测试小说的效果药理学调节剂增强纤毛AChM 3R介导的NO生物合成。在目标2中，我们在3xTgAD模型中检查脑血管纤毛和AChM 3R KO在BP和AD表现中的作用。我们预计，该项目的成功完成将为利用内皮细胞提供新的机会。 mAChR作为治疗干预措施的分子靶点，旨在预防HTN对人的有害影响脑血管和认知功能。