The role of the CXCR3 chemokine system in Alzheimer´s disease (AD)

炎症过程的失调被认为是导致阿尔茨海默病等神经退行性疾病进展的因素。趋化因子的大量表达，包括CXCRS配体CXCLIO，表明这些炎症分子在AD的发病机制中发挥了作用。我们自己的初步数据也表明了CXCRS在AD病理发展中的重要作用：CXCR3缺陷的APP/PS1小鼠的AD典型病理表现为Aü沉积减少和小胶质细胞激活。这表明CXCRS在AD-样病理的进展过程中是重要的，并可作为AD的治疗靶点。为了明确CXCRS在AD中的作用，我们初步比较了APP/PSICXCR3+/+转基因小鼠和APP/PSICXCR3-/-对照小鼠的组织学特征。我们将通过行为测试、APP处理的表征和流式细胞术来完成这一表征。将在体外检测吞噬细胞和神经元APP的处理，以剖析小胶质细胞与神经元CXCR3的功能方面。为了阐明CXCLIO的作用，将产生APP/PSICXCL10-/-转基因小鼠并对其进行鉴定。最后，我们将通过用CXCRS阻断小化合物治疗APP/PSI转基因小鼠来评估CXCRS阻断治疗的可能性。

Dysregulated inflammatory processes have been identified as contributors to the progression of neurodegenerative diseases like AD. The abundant expression of chemokines, including the CXCRS ligand CXCLIO, points toward a role of these inflammatory molecules in the pathogenesis of AD. Our own preliminary data points towards an important role of CXCRS in the development of AD pathology as well: CXCR3-deficient APP/PS1 mice have an attenuated ADtypical pathology with reduced Aß-deposifion and microglia activation. This suggests that CXCRS is important for the progression of AD-Iike pathology and can be a therapeufical target in AD. To define the role of CXCRS in AD, we preliminary characterized the histological features of APP/PSICXCR3+/+ transgenic mice compared with APP/PSICXCR3-/- controls. We will complete this characterization with behavioural testing, characterizafion of APP-processing and flow cytometry. Aß-phagocytes is and neuronal APP-processing will be examined in vitro to dissect the funcfional aspects of microglial versus neuronal CXCR3. To clarify the role of CXCLIO, APP/PSICXCL10-/- transgenic mice will be generated and characterized. Finally, we will evaluate the potential of a CXCRS-blocking therapy by treafing APP/PSI transgenic mice with a CXCRS blocking small compound.