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

项目摘要和摘要： 阿尔茨海默病和相关痴呆症(ADRD)是一种逐渐使人丧失能力的疾病 剥夺受影响的个体的认知功能，最终导致他们无法 进行日常生活的基本活动。大脑依赖于连续的和良好的调节 通过脑血流输送能量底物，这是通过精心设计完成的 神经血管控制机制，始终确保足够的大脑灌注量。这样的一个 一种称为功能性充血的机制，将局部神经活动与血液输送相结合 流动，需要组织纤溶酶原激活剂(TPA)才能完全表达，因为tPA能够 谷氨酸能突触活动中产生的强有力的血管扩张剂一氧化氮。 神经血管改变在ADRD病程的早期被观察到，并可能促进 认知障碍的表现。淀粉样β蛋白是AD的重要致病因素， 通过上调tPA抑制物PAI-1而抑制功能性充血 在tPA活性中。然而，PAI-1的细胞来源和鉴定仍不清楚 将为挽救淀粉样蛋白引起的神经血管功能障碍提供新的方法- 贝塔。血管周围巨噬细胞(PVM)是一种有别于小胶质细胞的脑内髓系细胞 位于血管周围空间，可产生大量的活性氧(ROS)。 它们是PAI-1上调的关键驱动因素。因此，我们将检验中心假设 PVM是PAI-1的主要来源，导致tPA缺乏，神经血管 由淀粉样β蛋白引起的功能障碍和认知障碍。这一假设将在3年内得到检验。 具体目的：(1)PVM是PAI-1的来源，介导tPA缺乏和神经血管 淀粉样蛋白-β诱导的解偶联，(2)PVM CD36和NOX2，它们与 在这些细胞中产生ROS，介导PAI-1的上调，以及(3)PVM PAI-1参与 对长期积累的淀粉样β蛋白的影响。这些具体目标将是 通过使用环法，包括体内和体外技术来完成。 这一应用将拓宽我们对有害物质细胞机制的认识基础 淀粉样β蛋白的神经血管效应。

PROJECT SUMMARY AND ABSTRACT: Alzheimer's disease and related dementias (ADRD) are disabling conditions that progressively deprive affected individuals of their cognitive functions, ultimately leading to their inability to perform basic activities of daily living. The brain depends on continuous and well-regulated delivery of energy substrates through the brain blood flow, which is accomplished by elaborate neurovascular control mechanisms that always ensure sufficient cerebral perfusion. One such mechanism, termed functional hyperemia, couples local neural activity with the delivery of blood flow and requires tissue plasminogen activator (tPA) for its full expression, since tPA enables the production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. Neurovascular alterations are observed early in the disease course of ADRD and may promote the expression of cognitive impairment. Amyloid-beta, a significant pathogenic contributor to AD, suppresses functional hyperemia by upregulating the tPA inhibitor PAI-1 resulting in a reduction in tPA activity. However, the cellular sources of PAI-1 remain unclear, and their identification would suggest new approaches to rescue the neurovascular dysfunction induced by amyloid- beta. Perivascular macrophages (PVM), brain resident myeloid cells distinct from microglia located in the perivascular space, can produce large amounts of reactive oxygen species (ROS) which are critical drivers of PAI-1 upregulation. Therefore, we will test the central hypothesis that PVM are the major source of the PAI-1 that leads to tPA deficiency, neurovascular dysfunction, and cognitive deficits induced by amyloid-beta. This hypothesis will be tested in 3 specific aims: (1) PVM are the source of PAI-1 mediating tPA deficiency and neurovascular uncoupling induced by amyloid-beta, (2) PVM CD36 and Nox2, which are responsible for the ROS production in these cells, mediate the PAI-1 upregulation, and (3) PVM PAI-1 contributes to the effects of long-term accumulation of amyloid-beta. These specific aims will be accomplished by employing tour de force approaches, including in vivo and in vitro techniques. The application will widen our knowledge basis for the cellular mechanisms of harmful neurovascular effects of amyloid-beta.