NOS2 and Alzheimer disease: In contrast, activation of TREM2-APOE signaling in AD results in a subset of microglia that display a ‘neurodegenerative phenotype’, characterized by suppression of homeostatic genes like Cx3cr1 and P2ry12 and upregulation of pro-inflammatory markers like Clec7a, Ccl5, Ccl2, IL1b, and Nos2. These neurodegenerative microglia are associated with neuritic plaques, degenerating neurons and trigger a loss of tolerogenic responses in EAE and ALS [21].