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

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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.