tPA and Cerebrovascular Regulation in a Model of β-amyloid Pathology

项目总结和摘要： 越来越多的证据表明脑血管的变化有助于大脑 阿尔茨海默氏痴呆症（AD）的潜在功能障碍。β淀粉样蛋白是AD的罪魁祸首， 对神经元和神经胶质有有害作用。β淀粉样蛋白也深刻地改变了 大脑微循环的变化然而，很少有人知道淀粉样蛋白β如何有助于 改变了神经血管的调节考虑到以下事实，这个问题特别重要： 大脑高度依赖于与其新陈代谢相匹配的无休止的血液供应， 需求因此，这项拨款申请的目标是研究淀粉样蛋白β如何改变 控制机制调节血液输送到大脑，并有助于大脑 功能障碍我们最近发现，组织纤溶酶原激活剂（tPA），一种酶， 以其参与血管纤维蛋白溶解而闻名，在以下机制中起关键作用： 通过其调节关键神经元-血管信号传导的能力来调节神经血管 涉及突触后NMDA受体（NMDAR）、神经元一氧化氮合酶的途径 （nNOS）和一氧化氮。因此，我们将检验以下假设： 导致β淀粉样蛋白诱导的神经血管失调和认知缺陷， 过表达淀粉样前体蛋白的小鼠。中心假设将在3中进行检验 具体目的：（1）降低tPA活性有助于神经血管调节的改变 （2）tPA活性降低有助于淀粉样蛋白β诱导的 通过损害nNOS衍生的一氧化氮产生的神经血管失调 NMDA受体，和（3）tPA活性降低有助于淀粉样蛋白病理学， 认知缺陷这些具体目标将通过采用多学科战略来实现 结合体外分子、生物化学、共聚焦和电子显微镜成像， 活体生理学和行为学方法。

PROJECT SUMMARY AND ABSTRACT: There is accumulating evidence that alterations in cerebral blood vessels contribute to brain dysfunction underlying Alzheimer's dementia (AD). Amyloid-beta is a major culprit in AD and has deleterious effects on neurons and glia. Amyloid-beta also profoundly alters the regulation of the cerebral microcirculation. However, little is known as to how amyloid-beta contributes to altering the neurovascular regulation. This issue is particularly important considering the fact that the brain is highly dependent on a ceaseless blood supply well matched to its metabolic needs. Therefore, the goal of this grant application is to investigate how amyloid beta alters the control mechanisms regulating the blood delivery to the brain and contributes to brain dysfunction. We have recently found that the tissue plasminogen activator (tPA), an enzyme best known for its involvement in vascular fibrinolysis, plays a key role in the mechanisms of neurovascular regulation via its ability to modulate a critical neuron-to-vasculature signaling pathway involving postsynaptic NMDA receptors (NMDAR), neuronal nitric oxide synthase (nNOS), and nitric oxide. Therefore, we will test the hypothesis that the reduction in tPA contributes to the neurovascular dysregulation and cognitive deficits induced by amyloid-beta in mice overexpressing the amyloid precursor protein. The central hypothesis will be tested in 3 specific aims: (1) reduced tPA activity contributes to the alteration in neurovascular regulation induced by amyloid-beta, (2) reduced tPA activity contributes to amyloid-beta-induced neurovascular dysregulation by impairing nNOS-derived nitric oxide production dependent on NMDA receptor, and (3) reduced tPA activity contributes to amyloid pathology and resulting cognitive deficits. These specific aims will be achieved by employing a multidisciplinary strategy combining in vitro molecular, biochemical, confocal and electron microscopic imaging, and in vivo physiological and behavioral approaches.