Chronic neurodegeneration is a major worldwide health problem, and it has been suggested that systemic inflammation can accelerate the onset and progression of clinical symptoms. A possible explanation is that systemic inflammation "switches" the phenotype of microglia from a relatively benign to a highly aggressive and tissue-damaging phenotype. The current study investigated the molecular mechanism underlying this microglia phenotype "switching." We show in mice with chronic neurodegeneration (ME7 prion model) that there is increased expression of receptors that have a key role in macrophage activation and associated signaling pathways, including TREM-2, Siglec-F, CD200R, and FcγRs. Systemic inflammation induced by LPS further increased protein levels of the activating FcγRIII and FcγRIV, but not of other microglial receptors, including the inhibitory FcγRII. In addition to these changes in receptor expression, IgG levels in the brain parenchyma were increased during chronic neurodegeneration, and these IgG levels further increased after systemic inflammation. γ-Chain-deficient mice show modified proinflammatory cytokine expression in the brain after systemic inflammation. We conclude that systemic inflammation during chronic neurodegeneration increases the expression levels of activating FcγR on microglia and thereby lowers the signaling threshold for Ab-mediated cell activation. At the same time, IgG influx into the brain could provide a cross-linking ligand resulting in excessive microglia activation that is detrimental to neurons already under threat by misfolded protein.