Fig. 1

Factors impacting microglial phenotype in the context of homeostasis and neurodegeneration. Adult microglia are characterized by the expression of P2ry12, Cx3cr1, and Tmem119, among others. In addition to their role in immune surveillance, microglia participate in central nervous system homeostasis and are known to release neurotrophic factors that promote neuronal health. During Alzheimer’s disease pathogenesis, microglia are activated by amyloid β through binding of TLR4 and, in a TREM2 dependent manner, downregulate expression of homeostatic genes and upregulate Apoe, Tyrobp, Trem2, and other genes, adopting the disease-associated microglia (DAM) program. DAM are effective at containing and phagocytosing amyloid β plaques. At the same time, DAM cease their neuroprotective functions and release neuroinflammatory factors such as IL-1β and TNFα that are directly damaging to neurons and lead to tau phosphorylation and subsequent cognitive decline. In addition to local factors, the peripheral immune system can modify these responses and induce the DAM program, indicating that this is a potential target through which the homeostatic and inflammatory balance can be modulated and perhaps used to promote beneficial outcomes in AD