OLIGOMERIC AB AND INFLAMMATION IN NEUROVASCULAR PATHOGENESIS IN AD

项目5：AD神经血管发病机制中的寡聚AB和炎症 在阿尔茨海默病（AD）中，β-淀粉样蛋白（AB）沉积在脑血管中是常见的， 越来越多的人认识到BBB功能障碍在许多神经退行性疾病中起着关键作用， 包括AD。该项目的重点是假设AB的寡聚体形式激活CD-14-toll样 受体4在BBB中的内皮细胞（EC）和血管平滑肌细胞（VSMC）上的表达。所得 炎症反应有助于纤维状AB的沉积，并诱导脑血管炎性反应。 包括邻近血管周围巨噬细胞和星形胶质细胞的级联反应。由此产生的慢性表达 促炎细胞因子，增加内皮细胞上的炎性细胞粘附分子，并减弱 营养因子受体介导的信号在神经血管单位。此外，由于长期接触 到AB寡聚体和随后的血管成分中纤维状AB的沉积，这些细胞保持在 准备好进一步激活的“启动状态”。第二个假设是慢性全身性炎症 加重脑血管系统的炎症状态。AB的寡聚体形式在 由于缺乏合适的治疗方法，血管系统中的炎症和变性在很大程度上仍然未知。 动物模型，以研究与AB血管沉积相关的病理学病变。我们将利用 APP 2576和Tg-SwDI小鼠，因为它们共同发展了广泛的脑血管病理学 在AD中发现的。目的1：AB的寡聚体形式是否与炎症的发生相关？ AD、唐氏综合征（DS）和APP/Tg小鼠的血管？目的2：AB的寡聚体形式 激活CD 14-TLR 4受体复合物？AB的寡聚体形式激活EC和VSMC吗？做 AB的寡聚体形式抑制EC和VSMCs中的生长因子信号传导？目的3：慢性全身性 炎症加剧低聚AB脑血管沉积并增加脑血管炎症？ 目的4：治疗策略：抗炎方法能否减轻炎症诱导的不良反应？ APP/Tg小鼠的血管系统中的事件？转染的间充质干细胞（MSC）表达 单链抗AB抗体减弱AB寡聚体介导脑血管炎症和变性？

Project# 5: Oligomeric AB and Inflammation in Neurovascular Pathogenesis in AD In Alzheimer disease (AD) beta-amyloid (AB) deposition in the cerebrovasculature is common and there is increasing recognition that dysfunction in the BBB plays a critical role in many neurodegenerative diseases, including AD. The focus of this project is on the hypothesis that oligomer forms of AB activate CD-14-toll-like receptor 4 on the endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in the BBB. The resulting inflammatory response contributes to the deposition of fibrillar AB and induces a cerebrovascular inflammatory cascade that encompasses adjacent perivascular macrophages and astrocytes. The resulting chronic expression of proinflammatory cytokines, increases inflammatory cell adhesion molecules on endothelial cells, and attenuates trophic factor receptor-mediated signaling in the neurovascular unit. Moreover, because of the chronic exposure to AB oligomers and the subsequent deposition of fibrillar AB in vascular elements, these cells remain in a "primed state" ready to be further activated. A secondary hypothesis is that chronic systemic inflammation exacerbates the inflammatory state of the cerebrovascular system. The role of oligomeric forms of AB in inflammation and degeneration in the cerebrovasculature remains largely unknown due to the lack of suitable animal models to investigate the pathological lesions associated with vascular deposition of AB. We will utilize APP2576 and Tg-SwDI mice because collectively they develop the broad spectrum of cerebrovascular pathology that are found in AD. Aim 1: Do oligomeric forms of AB correlate with the onset of inflammation in the cerebrovasculature in AD, Down Syndrome (DS), and APP/Tg mice? Aim 2: Do oligomeric forms of AB activate the CD14-TLR4 receptor complex? Do oligomeric forms of AB activate ECs and VSMCs? Do oligomeric forms of AB inhibit growth factor signaling in ECs and VSMCs? Aim 3: Does chronic systemic inflammation exacerbate cerebrovascular deposition of oligomeric AB and increase cerebrovascular inflammation? Aim 4: Therapeutic Strategies: Can anti-inflammatory approaches attenuate the inflammatory-induced adverse events in the cerebrovasculature in APP/Tg mice? Can transfected mesenchymal stem cells (MSCs) expressing a single chain anti-AB antibody attenuate AB oligomer-mediated cerebrovascular inflammation and degeneration?