Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy

Kevin R Nash, Daniel C Lee, Jerry B Hunt, Josh M Morganti, Maj-Linda Selenica, Peter Moran, Patrick Reid, Milene Brownlow, Clement Guang-Yu Yang, Miloni Savalia, Carmelina Gemma, Paula C Bickford, Marcia N Gordon, David Morgan
Neurobiology of Aging 2013, 34 (6): 1540-8
Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation. Experiments with fractalkine receptor null mice suggest that fractalkine signaling diminishes tau pathology, but exacerbates amyloid pathology. Consistent with this outcome, we report here that soluble fractalkine overexpression using adeno-associated viral vectors significantly reduced tau pathology in the rTg4510 mouse model of tau deposition. Furthermore, this treatment reduced microglial activation and appeared to prevent neurodegeneration normally found in this model. However, in contrast to studies with fractalkine receptor null mice, parallel studies in an APP/PS1 model found no effect of increased fractalkine signaling on amyloid deposition. These data argue that agonism at fractalkine receptors might be an excellent target for therapeutic intervention in tauopathies, including those associated with amyloid deposition.

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