J. Neurosci. 34, 12538–12546 (2014)

Microglia express a number of genes that have been implicated in the pathology of Alzheimer's disease (AD), which is characterized by extracellular accumulation of amyloid-β peptide (Aβ) peptides and intraneuronal aggregates of hyperphosphorylated tau. One of these genes encodes CX3CR1, a receptor expressed exclusively by microglia that binds either a membrane-anchored or a cleaved soluble form of a neuron-generated chemokine ligand, CX3CL1. CX3CR1 knockout ameliorates disease hallmarks in an AD mouse model (called APPPS1) via enhanced Aβ clearance but exacerbates tau phosphorylation and aggregation in a related tauopathy model (called hTau). To understand this discrepancy and dissect the roles of the membrane-anchored versus the soluble form of CX3CL1, Lee et al. generated APPPS1 mice that expressed only the soluble CX3CL1 and found no difference in Aβ deposition when compared to APPPS1 mice expressing no CX3CL1. However, when compared with CX3CL1-expressing APPPS1 mice, the soluble CX3CL1–expressing mice had increased intraneuronal tau phosphorylation. CX3CL1 knockout mice had similarly elevated intraneuronal tau phosphorylation but had reduced extracellular Aβ deposition. Transcriptomic experiments found three genes, encoding two inflammatory cytokines and an Aβ phagocytic receptor (MSR1), that were consistently altered in microglia from the four mice strains and that correlated with the effects on Aβ deposition. These results and experiments examining downstream signaling via p38 MAPK and Aβ uptake implicate the membrane-anchored CX3CL1 in the apparent opposing effects on AD pathologies via enhanced MSR1-dependent phagocytosis of Aβ and decreased MAPK activation.