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

描述(申请者提供)：这笔FIRCA拨款专注于与A2免疫疗法相关的神经免疫反应和小胶质细胞/胶质细胞的激活，A2是一种有前途的阿尔茨海默病(AD)疗法，目前正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大学(JHMI)阿尔茨海默病研究中心(ADRC)和智利卡特斯利卡大学(PUC)神经科学实验室之间的合作项目。ADRC神经病理学核心的具体目标包括支持与阿尔茨海默病相关的动物研究，该核心的研究人员一直从事A2免疫疗法的研究，并具有丰富的经验。在FIRCA申请中提出的研究需要评估接受A2抗体被动免疫的AD转基因小鼠模型的生化和形态变化。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神经炎症和小胶质细胞和神经胶质细胞在AD发病机制中的作用的研究。人们普遍认为A2的蓄积是阿尔茨海默病的主要原因之一。我们认为，除了A2相关的毒性外，慢性炎症激活引起的小胶质细胞损伤也是A2蓄积和神经元功能障碍的原因。基于这些概念，这一FIRCA应用程序提出了针对A2的被动免疫治疗的神经免疫反应的特征及其在A2沉积的转基因模型中的影响。免疫治疗可显著诱导小胶质细胞摄取A2。另一方面，清道夫受体参与A2的结合，介导神经胶质细胞的炎症反应。此外，这种反应受到促炎和抗炎细胞因子，即TGF2的调节。此外，促炎症细胞因子和抗炎细胞因子的表达以及它们的一些信号通路在衰老过程中都会发生改变，可能会导致神经胶质细胞调节的损害。我们的假设是，“清道夫受体和TGF2表达的变化是依赖于免疫治疗的A2清除和A2沉积转基因模型的认知改善的原因。”为了验证这一假设，我们将使用APPswe/PS1dE9转基因小鼠，这是一种A2脑沉积的模型。这些小鼠将接受慢性促炎刺激(LPS)和针对A2的被动免疫治疗。我们将评估炎症调节因子TGF2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。这些标记物将与吞噬活动和认知表现相关。本研究探讨与阿尔茨海默病发病机制相关的神经免疫机制，以及该疾病治疗策略的发展。 与公共卫生相关：阿尔茨海默病是一个世界性的重大健康问题，其影响将随着人口老龄化而增加。在接下来的几十年里，大多数阿尔茨海默氏症患者将来自发展中的国家(Ferri等人，2005年)。这就是智利将很快面临的情况，因为这种疾病的流行率正在急剧增加，但照顾这些患者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愈阿尔茨海默病。因此，像免疫疗法这样可以预防和阻止阿尔茨海默病进展的治疗方法的开发，对于改善公共卫生层面的管理至关重要。这项申请解决了与开发免疫疗法或阿尔茨海默氏症疫苗直接相关的问题。

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.