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

项目摘要和摘要： 越来越多的证据表明，脑血管的变化对大脑有贡献 阿尔茨海默病(AD)的潜在功能障碍。淀粉样β蛋白是AD和AD的主要罪魁祸首 对神经元和神经胶质细胞有有害影响。淀粉样β蛋白也深刻地改变了这种调节。 脑部微循环。然而，人们对淀粉样β蛋白是如何参与的却知之甚少。 改变神经血管的调节。考虑到这样一个事实，这个问题特别重要 大脑高度依赖与其新陈代谢相匹配的源源不断的血液供应 需要。因此，这项拨款申请的目标是调查淀粉样β蛋白是如何改变 调节血液输送到大脑并对大脑有贡献的控制机制 功能障碍。我们最近发现组织纤溶酶原激活物(TPA)，一种酶 以参与血管纤溶而闻名，在血管纤溶机制中起着关键作用 通过调节关键的神经元到血管信号的能力来调节神经血管的调节 涉及突触后NMDAR、神经元型一氧化氮合酶的通路 (NNOS)和一氧化氮。因此，我们将检验这样一个假设，即tPA的减少 淀粉样β蛋白致大鼠神经血管调节障碍和认知功能障碍 过度表达淀粉样前体蛋白的小鼠。核心假设将在3年内得到检验。 具体目的：(1)tPA活性降低有助于神经血管调节的改变 (2)tPA活性降低参与了淀粉样β蛋白的诱导 通过损害依赖于nNOS的一氧化氮的产生而引起的神经血管调节失调 NMDA受体，以及(3)tPA活性降低参与淀粉样蛋白病理并导致 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、生化、共聚焦和电子显微镜成像，并在 活体生理和行为方法。

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.