Scavenger Receptors Type-A of Microglia Promote Abeta Uptake After Abeta Immunot

描述（由申请人提供）：该FIRCA资助的重点是与针对A2的免疫疗法相关的神经免疫反应和小胶质细胞/胶质细胞活化，A2是一种有前途的阿尔茨海默病（AD）治疗方法，目前正在由几个研究小组进行临床试验。该应用程序是约翰霍普金斯医疗机构（JHMI）阿尔茨海默病研究中心（ADRC）神经病理学核心与智利天主教大学（PUC）神经科学实验室之间的合作。ADRC神经病理学核心的具体目标包括支持与AD相关的动物研究，该核心的研究者已经参与了针对A2的免疫治疗研究并具有丰富的经验。本FIRCA申请中提出的研究需要评估接受抗A2抗体被动免疫的AD转基因小鼠模型中的生化和形态学变化。这些变化将与认知和行为参数相关。PUC神经科学实验室专注于研究神经炎症以及小胶质细胞和胶质细胞在AD发病机制中的作用。人们普遍认为，A2的积累是AD的主要原因之一。我们认为，除了A2相关的毒性，小胶质细胞损伤来自慢性炎症激活是负责A2积累和神经元功能障碍。基于这些概念，该FIRCA申请提出表征对A2的被动免疫疗法的神经免疫应答及其在A2沉积的转基因模型中的作用。免疫疗法极大地诱导小胶质细胞摄取A2。另一方面，清道夫受体（SR）参与A2的结合并介导胶质细胞的炎症反应。此外，这种反应由促炎和抗炎细胞因子即TGF 2调节。此外，促炎细胞因子和抗炎细胞因子的表达及其一些信号通路在衰老过程中会发生变化，并可能导致神经胶质细胞调节受损。我们的假设是，“清道夫受体和TGF-2表达的变化是A2沉积转基因模型上免疫治疗依赖性A2清除和认知改善的原因。“为了评估这一假设，我们将使用APPswe/PS1 dE 9转基因小鼠，一种A2脑沉积模型。小鼠将暴露于慢性促炎刺激（LPS）和针对A2的被动免疫疗法。我们将评估炎症调节因子TGF-2及其信号通路的表达，以及已知结合A2的清道夫受体的表达和功能水平。这些标志物将与吞噬活性和认知表现相关。本研究涉及AD发病机制相关的神经免疫机制，也为这种疾病的治疗策略的发展。 公共卫生相关性：阿尔茨海默病是一个严重的全球性健康问题，其影响将随着人口老龄化而增加。在未来几十年中，处于发展道路上的国家将拥有大多数阿尔茨海默病患者（Ferri等人，2005年）的报告。这是智利即将面临的情况，因为这种疾病的流行率正在急剧上升，但照顾这些病人的资源现在和将来都非常稀缺。目前，还没有有效的方法来预防或治疗阿尔茨海默病。因此，开发与预防和阻止阿尔茨海默病进展相关的免疫疗法等治疗方法对于改善公共卫生水平的管理至关重要。本申请解决了与阿尔茨海默病的免疫疗法或疫苗的开发直接相关的问题。

DESCRIPTION (provided by applicant): This FIRCA grant focuses on the neuroimmune response and microglial/glial activation associated with immunotherapy against A2, a promising therapy for Alzheimer's disease (AD) presently under clinical trial by several research groups. This application is collaboration between the Neuropathology Core of the Johns Hopkins Medical Institutions (JHMI) Alzheimer's disease Research Center (ADRC) and the Neuroscience Laboratory at the Pontificia Universidad Catslica de Chile (PUC). The specific aims of the ADRC Neuropathology Core include the support of animal studies relevant to AD and investigators of this Core have been engaged and are experienced in studies of immunotherapy against A2. The studies proposed in this FIRCA application entail assessments of biochemical and morphological changes in a transgenic mouse model of AD receiving passive immunization with antibodies against A2. These changes will be correlated with cognitive and behavioral parameters. The PUC Neuroscience Laboratory focuses on the study of neuroinflammation and the role of microglial and glial cells in the pathogenesis of AD. It has been widely proposed that accumulation of A2 is one of the major causes of AD. We believe that in addition to A2-related toxicity, microglial cell impairment derived from chronic inflammatory activation is responsible for both A2 accumulation and neuronal dysfunction. Based on these concepts, this FIRCA application proposes to characterize the neuroimmune response to passive immunotherapy against A2 and its effects in a transgenic model of A2 deposition. Immunotherapy greatly induces A2-uptake by microglial cells. On the other hand, scavenger receptors (SR) are involved in the binding of A2 and mediating the inflammatory response of glial cells. Furthermore, this response is modulated by pro- and anti- inflammatory cytokines, i.e. TGF2. Moreover, the expression of both pro- and anti-inflammatory cytokines and some of their signaling pathways are modified in aging and potentially could result in the impairment of glial cell regulation. Our hypothesis is that "changes on the expression of scavenger receptors and TGF2 are responsible for immunotherapy-dependent A2 clearance and cognitive improvement on a transgenic model of A2 deposition." In order to assess this hypothesis, we will use APPswe/PS1dE9 transgenic mice, a model of A2 brain deposition. The mice will be exposed to a chronic pro-inflammatory stimulus (LPS) and passive immunotherapy against A2. We will evaluate the expression of the inflammation modulator TGF2 and its signaling pathway as well as the expression and functional levels of scavenger receptors known to bind A2. Those markers will be correlated with phagocytic activity and cognitive performance. This study addresses neuroimmune mechanisms relevant to the pathogenesis of AD and also to the development of therapeutic strategies for this disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a significant health problem worldwide and its impact will increase as the population ages. It is countries on their way to development which will have most of the Alzheimer's patients in the next few decades (Ferri et al., 2005). This is the situation that Chile will soon face since the prevalence of the disease is sharply increasing, but the resources to care for these patients are and will be very scarce. Currently, there is no effective way to prevent or cure Alzheimer's Disease. Therefore, the development of treatments like Immunotherapy that could be relevant for both prevention and arresting the progression of Alzheimer's disease is critical for improving its management at the public health level. This application addresses issues directly relevant to the development of immunotherapy or a vaccine for Alzheimer's.