RESEARCH ARTICLE Neuronal Cx3cr1 Deficiency Protects against

Cx3cr1, the receptor for the chemokine Cx3cl1 (fractalkine), has been implicated in the pro-gression and severity of Alzheimer’s disease-like pathology in mice, but the underlying mechanisms remain unclear. A complicating factor is that Cx3cr1 has been demonstrated in both neurons and microglia. Here, we have dissected the differences between neuronal and microglial Cx3cr1, specifically by comparing direct amyloid-β-induced toxicity in cul-tured, mature, microglia-depleted hippocampal neurons from wild-type and Cx3cr1-/-mice. Wild-type neurons expressed both Cx3cl1 and Cx3cr1 and released Cx3cl1 in response to amyloid-β. Knockout of neuronal Cx3cr1 abated amyloid-β-induced lactate dehydrogenase release. Furthermore, amyloid-β differentially induced depression of pre- and postsynaptic components of miniature excitatory postsynaptic currents, in a peptide conformation-depen-dent manner. Knockout of neuronal Cx3cr1 abated effects of both amyloid-β conformational states, which were differentiable by aggregation kinetics and peptide morphology. We ob-tained similar results after both acute and chronic treatment of cultured neurons with the Cx3cr1 antagonist F1. Thus, neuronalCx3cr1may impact Alzheimer’s disease-like patholo-gy by modulating conformational state-dependent amyloid-β-induced synaptotoxicity