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General statements
Investigator

Martin Fuhrmann

Title

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

Summary

Alzheimer’s disease (AD) is characterized by the deposition of aggregated Aβ 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 that is expressed exclusively on microglia in the brain binds the neuronally expressed ligand fractalkine/CX3CL1. The ligand exists in a membrane bound and a soluble form mediating chemotaxis and migration of microglial cells. In the triple transgenic mouse model of AD (3xTg-AD) that exhibits a combined Aβ and tau pathology closely mimicking human AD, neuron loss was prevented by CX3CR1 knockout. Therefore, CX3CR1expressed 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, as well as microglial migration and fine process motility. Preliminary data of the applicant shows that CX3CR1 knockout may have a beneficial effect on the behavior of 3xTg-AD mice. We hypothesize that treatment with CX3CR1 antagonists reverts AD induced behavioral changes in these mice. Treatment with antibodies directed against CX3CR1 and small molecule antagonists will be carried out to test their effects on AD-related pathology and behavior.