OLIGOMERIC AB AND INFLAMMATION IN NEUROVASCULAR PATHOGENESIS IN AD

AD 神经血管发病过程中的低聚 AB 和炎症

基本信息

批准号：
7347990
负责人：
David Hastings Cribbs
金额：
$ 24.59万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7347990
关键词：
Adverse event Age Agonist Alzheimer&apos s Disease Amyloid beta-Protein Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigen-Antibody Complex Archives Astrocytes Attenuated Autopsy Binding Blood - brain barrier anatomy Blood Vessels Bone Marrow C5a anaphylatoxin receptor CD14 gene Cell Adhesion Molecules Cells Cerebral hemisphere hemorrhage Cerebrovascular system Cerebrum Chemicals Chronic Collaborations Complement Complement 3a Complement 5a Complement Activation Complex Dementia Deposition Down Syndrome Elderly Elements Endothelial Cells Event Exposure to Functional disorder Growth Factor Head Health Hemorrhage Human Immune system Immunotherapy Impaired cognition Incidence Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Insulin Insulin Resistance Insulin-Like Growth Factor I Interleukin-16 Interleukin-6 Knockout Mice Learning Lesion Life Maps Measures Mediating Memory impairment Mesenchymal Stem Cells Minocycline Modeling Molecular Conformation Monitor Monozygotic twins Mus Neurodegenerative Disorders Neuroglia Neuronal Dysfunction Non-Insulin-Dependent Diabetes Mellitus Pathogenesis Pathology Periodontal Diseases Peripheral Pharmaceutical Preparations Phenotype Play Preparation Principal Investigator Proteins Range Relative (related person)Reporter Reporting Risk Risk Factors Role Series Signal Transduction Site Smooth Muscle Myocytes Specimen System Teenagers Testing Tg2576 Therapeutic Tissues Trophic Factor Receptor Vascular Dementia Vascular Endothelial Cell abeta accumulation age related anakinra behavior test cerebrovascular clinical phenotype cognitive function cyclooxygenase 2 cytokine improved insulin sensitivity interest macrophage mild neurocognitive impairment modifiable risk mouse model mouse toll-like receptor 4 neuropathology neurovascular unit novel programs receptor research study rosiglitazone toll-like receptor 4 vascular inflammation

项目摘要

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?

项目＃5：AD中神经血管发病机理中的低聚AB和炎症在阿尔茨海默氏病（AD）β-淀粉样蛋白（AB）沉积中，脑桥梁的沉积很常见，并且有越来越多地认识到，BBB中功能障碍在许多神经退行性疾病中起着关键作用，包括广告。该项目的重点是假设AB的低聚物形式激活CD-14 Toll样内皮细胞（EC）和血管平滑肌细胞（VSMC）上的受体4。结果炎症反应有助于原纤维AB的沉积并诱导脑血管炎症级联，包括相邻的周围巨噬细胞和星形胶质细胞。由此产生的慢性表达促炎细胞因子，增加内皮细胞上炎症细胞粘附分子，并减弱营养因子受体介导的神经血管单元的信号传导。而且，由于长期暴露对于AB低聚物和随后的血管元素中的沉积，这些细胞保留在A中准备进一步激活的“底漆状态”。次要假设是慢性全身性炎症加剧脑血管系统的炎症状态。 AB的低聚形式的作用由于缺乏合适的动物模型研究与AB血管沉积有关的病理病变。我们将利用 App2576和TG-SWDI小鼠，因为它们统称为脑血管病理的广泛范围在AD中发现。目标1：AB的低聚形式是否与炎症发作相关 AD，唐氏综合症（DS）和APP/TG小鼠的大脑脑血管形系统？目标2：AB的低聚形式激活CD14-TLR4受体复合物？ AB的低聚形式是否激活ECS和VSMC？做 AB的低聚形式抑制ECS和VSMC中的生长因子信号传导？目标3：慢性系统性炎症加剧了低聚AB的脑血管沉积并增加脑血管炎症？目标4：治疗策略：抗炎方法可以减轻炎症引起的不良 APP/TG小鼠大脑脑管中的事件？可以转染的间质干细胞（MSC）表达A 单链抗AB抗体减弱AB寡聚介导的脑血管炎症和变性？