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P2Y purinoceptor 12 (P2Y12R) is a G-protein coupled receptor that mediates the movement of microglia toward purinergic nucleotides—ADP and ATP—that may be released by damaged cells (Haynes et al., 2006). P2Y12R is frequently said to be a marker of homeostatic microglia. While the presence of this receptor distinguishes microglia from other types of macrophages (Butovsky et al., 2014; Haynes et al., 2006; Mildner et al., 2017), it is less clear whether it distinguishes homeostatic microglia from microglia responding to CNS disease or injury. P2ry12 expression, measured at the mRNA level, was found to be downregulated in transgenic mouse models of amyloidosis (Keren-Shaul et al., 2017; Krasemann et al., 2017; Zhou et al., 2020). By contrast, in one study, expression of P2YR12 was elevated in the brains of human AD cases, compared with controls (Zhou et al., 2020). While a second study of human specimens found no difference in P2YR12 mRNA levels between AD cases and non-demented elderly controls, P2Y12R protein levels were found to be reduced in AD (Walker et al., 2020). Multiple studies have reported the selective loss of P2Y12R immunoreactivity from microglia in the immediate vicinity of amyloid plaques (Mildner et al., 2017; Kenkhuis et al., 2022; Walker et al., 2020). P2Y12R immunoreactivity was seen in microglia with morphological features associated with activation, as well as in presumed homeostatic microglia (Kenkhuis et al., 2022; Walker et al., 2020).