Abstract: Adult microglia, by continuously sensing changes in their environment and communicating with nearly all brain cell types, are considered to be the immune sentinels of the brain. In the healthy central nervous system (CNS), microglia display a unique molecular homeostatic signature (i.e., Tmem119, P2ry12, Sall1, Siglech, Gpr34, and Hexb) (Figure 1A). These homeostatic microglia are distinct from activated microglia, the signature of which is highly microenvironmentand cellular context-dependent (Butovsky and Weiner, 2018; Paolicelli et al., 2022; Figure 1). The type and severity of insult, as well as the duration of stimulation, could influence either the beneficial or detrimental nature of the microglial response. On one hand, microglia could exert a protective function through phagocytosis and clearance of pathological protein aggregates. On the other hand, an excessive uptake of protein aggregates by microglia could lead to impairment of microglial phagocytic ability, induction of neuroinflammation, and eventually neurodegeneration. Neurodegenerative diseases, chronic neuroinflammatory states, and advanced aging could each induce dyshomeostatic profiles that can share some similarities while possessing distinct gene expression profiles (e.g., microglial neurodegenerative phenotype, MGnD; diseaseassociated microglia, DAM; aging-related microglia) (Paolicelli et al., 2022). This switch to a dyshomeostatic profile is reflected by an increased expression of neurodegenerative microglial genes (i.e., Apoe, Clec7a, Itgax, Lgals3, and Cst7; Figure 1C) tightly coupled with the downregulation of the above-mentioned microglial homeostatic genes.