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.

项目摘要随着晚期阿尔茨海默氏病的患病率继续增加，了解机械这种疾病的原因变得越来越重要。最近的临床研究已将刚度增加在记忆和阿尔茨海默氏病损害的大动脉中。假设这些关系是大动脉刚度引起的脑血管功能障碍的结果。大动脉刚度铅增加脑血管中压力和血流的搏动性更大，已知会引起血管损害。大脑动脉和微脉管系统功能障碍与认知障碍和大阿尔茨海默氏病与疾病相关的神经病理学。此外，淀粉样蛋白β（Aβ）诱导脑血管损害和脑血管障碍会增加Aβ的积累，从而产生一个恶性循环脑血管功能障碍和神经病理学。拟议研究的目的是提供第一个证明 - 概念表明，大动脉刚度与年龄相关的增长，与较大的Aβ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。实现这一目标目标，我们将采用大型大动脉刚度和更大的Aβ产生的转基因小鼠模型，如并使用药物干预来防止大动脉刚度与年龄相关的增加。在AIM 1中，我们将评估大动脉刚度与Aβ结合对认知功能障碍和阿尔茨海默氏病与疾病有关的神经病理学。在AIM 2中，我们将确定大动脉刚度的影响与Aβ结合，在脑血流和脑血管反应性和结构完整性上。在AIM 3中，我们将确定大动脉刚度和更大的脑动脉搏动性铅的候选机制脑血管功能障碍。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。这通过完成拟议的目标将获得的知识将为未来的研究提供信息，以识别新的疗法。预防或衰减阿尔茨海默氏病的靶标。