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

• Applicant: Privatdozent Dr. Marcus Müller
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2011 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 33995431

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.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 177: Innate Immunity in Chronic Neurodegeneration