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

项目摘要 随着迟发性阿尔茨海默病的患病率不断增加，了解其机制 这种疾病的病因正变得越来越重要。最近的临床研究表明， 与记忆力受损和阿尔茨海默氏症有关。据推测，这些关系 是大动脉僵硬引起的脑血管功能障碍的结果。大动脉僵硬度增加电极导线 脑血管系统中的压力和血流的更大脉动性，这已知会引起血管 损害脑动脉和微血管功能障碍与认知障碍有关， 老年痴呆症相关的神经病理学此外，淀粉样蛋白-β（Aβ）诱导脑血管 损伤，脑血管损伤增加Aβ积累，从而形成一个恶性循环， 脑血管功能障碍和神经病理学。这项研究的目的是提供第一个证据- 概念证据表明，年龄相关的大动脉僵硬度增加与Aβ升高协同作用 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 为了达到这一目标，我们将采用转基因小鼠模型，其大动脉僵硬度更大，Aβ产量更高， 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联合对认知功能障碍的影响， 阿尔茨海默病相关的神经病理学。在目标2中，我们将确定大动脉僵硬度的影响， 与Aβ组合，对脑血流量和脑血管反应性和结构完整性的影响。在目标3中， 我们将确定大动脉僵硬度和更大的脑动脉搏动性导致 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， 以及进行脑动脉和微血管内皮细胞的转录组分析。的 通过完成拟议目标获得的知识将为未来的研究提供信息，以确定新的治疗方法， 用于预防或减轻迟发性阿尔茨海默病的靶点。

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.