Role of perictyte nanotubes in age-related neurovascular dysfunction

项目总结 阿尔茨海默病和阿尔茨海默病相关性痴呆的特征是 神经功能和相关的认知功能下降。虽然神经元本身的变化很重要，但最近 我们小组和其他人的发现表明，致病机制的另一个主要因素： 神经血管偶联。在阿尔茨海默病中，神经元和血管之间的信号似乎断裂 伴发血管反应缺陷、脑淀粉样血管病变和结构性血管病变 改装。然而，对这些变化的细胞或分子基础知之甚少。在这项提案中，我们 确定在衰老和阿尔茨海默氏症的背景下负责维持血管完整性的关键机制 利用极易驯服的小鼠视网膜。我们已经表明，不同的视网膜神经元类型表现出不同的 与年龄和阿尔茨海默病相关的营养不良，多巴胺能神经元是中心靶点。在……里面 同样，我们的数据现在显示，神经变化伴随着明显的血管营养不良， 对周细胞及其新的纳米管状过程的特殊破坏。此外，使用遗传和 我们和其他人的药理学方法表明，多巴胺可以直接影响血管 组织和功能，并向周细胞发出信号。这些数据表明，阿尔茨海默氏症改变了神经- 多巴胺驱动的周细胞结构和功能的下降导致血管偶联。在目标1中，我们确定如何 阿尔茨海默病调节血管系统的结构和功能，特别关注周细胞。我们测试 周细胞改变伴随着血管血流动力学功能下降的假说， 偶联纳米管的丢失，以及局部相关的神经衰退。在目标2中，我们研究神经信号。 导致血管结构和功能下降的缺陷。我们的初步数据显示，多巴胺能 阿尔茨海默病患者的神经元减少，而多巴胺是维持血管完整性所必需的。 因此，我们测试了多巴胺信号减弱是阿尔茨海默氏症患者血管功能障碍的原因这一观点 可以针对疾病进行治疗，以减轻血管病变。这些研究将导致确定 阿尔茨海默病神经血管功能障碍的分子通路可能最终有用 用于预防发病机制。

PROJECT SUMMARY Alzheimer’s disease and Alzheimer’s disease associated dementias are characterized by marked alterations in neural function and associated cognitive decline. Though changes to neurons themselves are important, recent findings by our group and others suggest another major contributor to pathogenesis: alterations to neurovascular coupling. In Alzheimer’s disease, signaling between neurons and vessels appears to break down, accompanied by defects in vessel responses, cerebral amyloid angiopathy, and structural vascular alterations. However, little is known about the cellular or molecular basis of these changes. In this proposal, we identify a key mechanism responsible for maintaining vessel integrity in the context of aging and Alzheimer’s using the superbly tractable murine retina. We have shown that different retina neuron types exhibit distinct age- and Alzheimer’s disease-related dystrophies, and that dopaminergic neurons are a central target. In parallel, our data now reveal that neural changes are accompanied by distinct vascular dystrophies, with particular disruption to pericytes and their novel nanotube-like processes. Further, using genetic and pharmacological methods we and others have shown that dopamine can directly influence vascular organization and function and signal to pericytes. These data suggest that Alzheimer’s disease alters neuro- vascular coupling via declines in dopamine driven pericyte structure and function. In Aim 1, we determine how Alzheimer’s disease regulates vasculature structure and function, with a particular focus on pericytes. We test the hypothesis that pericyte alterations are accompanied by functional declines in vascular hemodynamics, loss of coupling nanotubes, and locally associated neural decline. In Aim 2, we examine the neural signaling defects causal to vascular structure and functional declines. Our preliminary data suggest that dopaminergic neurons are reduced in Alzheimer’s disease, and that dopamine is required for maintaining vessel integrity. We thus test the idea that declines in dopamine signaling are causal to vasculature dysfunction in Alzheimer’s disease and can be targeted to mitigate vascular pathology. These studies will lead to the identification of molecular pathways that drive neurovascular dysfunction in Alzheimer’s disease that may ultimately be useful for preventing pathogenesis.