Microglia lose their homeostatic function during neurodegenerative disorders. In Immunity, Butovsky and colleagues show that in mouse models of amyotrophic lateral sclerosis, Alzheimer's disease and multiple sclerosis, the neurodegenerative phenotype of microglia is triggered by activation of the receptor TREM2–apolipoprotein E (APOE) pathway. This phenotype is characterized by the suppression of TGF-β-dependent genes encoding homeostatic molecules, such as Sall1 and Tgfbr1, and the upregulation of genes encoding inflammatory molecules, including Apoe and Clec7a, and is distinct from microglial activation induced by lipopolysaccharide or the cytokine IFN-γ. The expression of APOE and Clec7a increases in microglia situated in close proximity to amyloid-b plaques in humans and mice and is induced by the injection of apoptotic neurons but not by Escherichia coli or zymosan. The neurodegenerative phenotype is not induced in Apoe−/− or Trem2−/− microglia after the phagocytosis of apoptotic neurons, and in contrast to wild-type microglia, Apoe−/− microglia from the spinal cord of mice at the peak of experimental autoimmune encephalomyelitis suppress T cell proliferation. As such, APOE might inhibit a tolerogenic phenotype in microglia.

Immunity 47, 566–581 (2017)