Role of perictyte nanotubes in age-related neurovascular dysfunction

项目摘要 阿尔茨海默氏病和阿尔茨海默氏病相关痴呆的特征在于， 神经功能和相关的认知能力下降。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研究结果表明，发病机制的另一个主要贡献者： 神经血管耦合在阿尔茨海默病中，神经元和血管之间的信号似乎中断了 下，伴有血管反应缺陷、脑淀粉样血管病和结构性血管病变， 改变。然而，人们对这些变化的细胞或分子基础知之甚少。在本提案中，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 用的是极其易处理的老鼠视网膜。我们已经证明，不同的视网膜神经元类型表现出不同的 年龄和阿尔茨海默病相关的营养不良，多巴胺能神经元是一个中心目标。在 与此同时，我们的数据显示，神经系统的变化伴随着明显的血管营养不良， 特别是破坏周细胞及其新型的纳米管样过程。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， 组织和功能以及向周细胞发出信号。这些数据表明，阿尔茨海默病改变了神经- 通过多巴胺驱动的周细胞结构和功能下降的血管偶联。在目标1中，我们确定如何 阿尔茨海默病调节血管结构和功能，特别关注周细胞。我们测试 假设周细胞的改变伴随着血管血流动力学的功能下降， 耦合纳米管的损失和局部相关的神经衰退。在目标2中，我们研究了神经信号 导致血管结构和功能下降的缺陷。我们的初步数据表明多巴胺能 神经元在阿尔茨海默病中减少，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的下降是阿尔茨海默氏症血管功能障碍的原因的想法 疾病，并且可以有针对性地减轻血管病理。这些研究将有助于确定 在阿尔茨海默病中驱动神经血管功能障碍的分子途径， 预防发病。

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.