Role of the microglial chemokine receptor CX3CR1 in Alzheimer´s disease

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

Alzheimer's disease (AD) is characterized by the deposition of aggregated Aß and tau proteins, as well as by cognitive decline presumably caused by synapse and neuron loss. AD pathology is accompanied by a prominent neuroinflammatory component of astro- and microgliosis which may also contribute significantly to the disease outcome. The chemokine receptor CX3CR1, exclusively expressed on brain microglia, binds the neuronally expressed ligand fractalkine/CX3CL1, thereby mediating Chemotaxis and migration of microglial cells. In the triple transgenic mouse model of AD (3xTg-AD) that exhibits a combined Aß and tau pathology, neuron loss was prevented by CX3CR1 knockout. Therefore, CX3CR1 expressed on brain microglia plays a critical role in AD pathogenesis. For this application we are going to clarify the effect of CX3CR1 knockout on AD-pathology and behavior. Especially, the effect of CX3CR1 knockout on dendritic spine density will be analyzed by Two-photon in vivo imaging. Preliminary data of the applicant shows that CX3CR1 knockout may have a beneficial effect on behavior. Treatment with antibodies directed against CX3CR1 and small molecule antagonists will be carried out to test their effects on AD-related pathology and behavior.

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