Large artery stiffness and cerebrovascular dysfunction: Implications for cognitive impairment and neuropathology

大动脉僵硬度和脑血管功能障碍：对认知障碍和神经病理学的影响

基本信息

批准号：
10374072
负责人：
Ashley Elizabeth Walker
金额：
$ 43.3万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374072
关键词：
Abeta synthesis Advanced Glycosylation End Products Affect Aging Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Aorta Area Arteries Attenuated Blood Pressure Blood Vessels Blood capillaries Blood flow Brain Carotid Arteries Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Clinical Research Data Dementia Development Disease Elastin Elderly Endothelial Cells Functional disorder Future Gene Expression Goals Impaired cognition Impairment Intervention Knowledge Late Onset Alzheimer Disease Lead Learning Link Measures Memory Memory impairment Methods Modeling Mus Mutation Nerve Degeneration Neurons Oxidative Stress Pathology Pharmacology Phenotype Prevalence Prevention Pulse Pressure Pyridoxamine Research Risk Risk Factors Role Source Testing Therapeutic Thinness Time Tissues Transgenic Mice Vascular Diseases Wild Type Mouse abeta accumulation age related aging brain arterial stiffness arteriole attenuation blood-brain barrier permeabilization cerebral artery cerebral microbleeds cerebral microvasculature cerebrovascular endothelial dysfunction human subject inhibitor innovation mouse model neuroinflammation neuropathology new therapeutic target novel presenilin-1 pressure prevent transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY As the prevalence of late-onset Alzheimer’s disease continues to increase, understanding the mechanistic causes of this disease is becoming increasingly critical. Recent clinical studies have linked increased stiffness of the large arteries to both impaired memory and Alzheimer’s disease. It is hypothesized that these relations are a result of large artery stiffness-induced cerebrovascular dysfunction. Increased large artery stiffness leads to greater pulsatility of pressure and blood flow in the cerebral vasculature, which is known to cause vascular damage. Dysfunction of the cerebral arteries and microvasculature is associated with cognitive impairment and greater Alzheimer’s disease-related neuropathology. Furthermore, amyloid-β (Aβ) induces cerebrovascular damage, and cerebrovascular impairment increases Aβ accumulation, thus creating a vicious cycle of cerebrovascular dysfunction and neuropathology. The goal of the proposed studies is to provide the first proof- of-concept evidence that age-related increases in large artery stiffness, synergistically with greater Aβ production, lead to cognitive impairment, neuropathology, and cerebrovascular dysfunction. To accomplish this goal, we will employ transgenic mouse models of greater large artery stiffness and greater Aβ production, as well as use a pharmacological intervention to prevent age-related increases in large artery stiffness. In Aim 1, we will assess the effects of large artery stiffness, in combination with Aβ, on cognitive dysfunction and Alzheimer’s disease-related neuropathology. In Aim 2, we will determine the effect of large artery stiffness, in combination with Aβ, on cerebral blood flow and cerebral vascular reactivity and structural integrity. In Aim 3, we will identify candidate mechanisms by which large artery stiffness and greater cerebral artery pulsatility lead to cerebrovascular dysfunction. To do so, we will examine the role and source(s) of vascular oxidative stress, as well as perform transcriptome analysis of cerebral arteries and microvascular endothelial cells. The knowledge to be gained by completing the proposed aims will inform future studies to identify novel therapeutic targets for the prevention or attenuation of late-onset Alzheimer’s disease.

项目概要随着迟发性阿尔茨海默病的患病率持续增加，了解其发病机制最近的临床研究表明，这种疾病的病因与僵硬增加有关。大动脉的损伤会导致记忆力受损和阿尔茨海默病。是大动脉僵硬度引起的脑血管功能障碍的结果。脑血管系统中压力和血流的更大脉动，已知这会导致血管性脑动脉和微血管的功能障碍与认知障碍和认知障碍有关。此外，β-淀粉样蛋白（Aβ）会诱发脑血管疾病。损伤和脑血管损伤会增加Aβ的积累，从而形成恶性循环脑血管功能障碍和神经病理学的研究目的是提供第一个证据- 概念证据表明，与年龄相关的大动脉硬度增加，与更大的 Aβ 具有协同作用产生，导致认知障碍、神经病理学和脑血管功能障碍。为了实现这一目标，我们将采用具有更大大动脉硬度和更多 Aβ 产生的转基因小鼠模型，如以及使用药物干预来预防与年龄相关的大动脉僵硬度增加。在目标 1 中，我们将评估大动脉僵硬度与 Aβ 结合对认知功能障碍和在目标 2 中，我们将确定大动脉僵硬度的影响。与 Aβ 结合，可影响脑血流量、脑血管反应性和结构完整性。我们将确定大动脉僵硬度和更大的脑动脉搏动导致的候选机制为此，我们将研究血管氧化应激的作用和来源，以及对脑动脉和微血管内皮细胞进行转录组分析。通过完成拟议目标所获得的知识将为未来的研究提供信息，以确定新的疗法预防或减轻迟发性阿尔茨海默病的目标。