It appears that one of the reasons for Aβ accumulation in Alzheimer’s disease is the failure of microglia to react properly. As mentioned, inflammation limits the phagocytic potential of microglia [127], but does this occur in vivo? Early on in disease pathogenesis, there does seem to be an attempt to clear Aβ. Jimenez et al.[132] observed at 6 months, when Aβ begins to accumulate in the APP/PS1 Alzheimer’s disease mouse model, that there were YM1+ cells present in the CNS; however, by 18 months YM1 mRNA levels decreased and there was a massive upregulation in inflammatory factors, suggesting a switch from M2 to M1 as pathology worsened [132]. This is consistent with the idea that microglia become less responsive to M2 induction signals as they age, perhaps owing to an age-associated decrease in IL-4Rα levels [133]. Correspondingly, in older, non-diseased mice there is downregulation of receptors associated with Aβ engulfment, such as scavenger receptor A and the Aβ degradation enzymes Nep, IDE, and MMP-9 [134]. These observations suggest that the Aβ induced inflammatory environment, combined with age-associated effects on microglia, lead to a situation where M1 cells predominate and microglia lose the ability to switch phenotypes and mitigate damage.
