TREM2 in Alzheimer disease

Several variants in TREM2 (triggering receptor expressed on myeloid cells 2), including an Arg47His mutation, are associated with increased risk of Alzheimer disease (AD). Two recent papers have examined the effect of Trem2 deficiency in mouse models of AD (APP/PS1 and 5XFAD mice) but have found contrasting roles for TREM2 in neurodegeneration. Jay et al. showed that TREM2 expression is selectively upregulated in myeloid cells that accumulate around β-amyloid deposits in the brains of APP/PS1 and 5XFAD mice, as well as in human AD brain tissue. In APP/PS1 mice, TREM2 was shown to be exclusively expressed by CD11b⁺F4/80⁺CD45^hi macrophages, which are thought to be derived from peripheral monocytes. Trem2^−/− APP/PS1 mice had greatly reduced numbers of plaque-associated CD45⁺ macrophages but there was no effect on the number of cells expressing P2RY12, which is a purinergic receptor expressed by microglia. These mice had reduced inflammation, ameliorated β-amyloid deposition in the hippocampus, and reduced astrocytosis and microtubule-associated protein tau pathology compared with controls. These data suggest that TREM2 has a detrimental role in AD pathology. By contrast, Wang et al. suggested that the cells expressing increased TREM2 in 5XFAD mice during β-amyloid deposition are microglia. Furthermore, TREM2 deficiency in 5XFAD mice resulted in increased β-amyloid deposition in the hippocampus compared with control mice. This increased deposition was suggested to be due to dysfunctional microglia, which did not accumulate around β-amyloid plaques and became apoptotic rather than activated. Further analysis showed that TREM2 recognizes anionic and zwitterionic lipids that are exposed during β-amyloid deposition and that the Arg47His mutation reduced the ability of TREM2 to bind anionic ligands. These data suggest that TREM2 senses damage-associated lipids and sustains a protective microglial response. Whether the differences in the role of TREM2 in AD described in these studies are due to differences in the rate of β-amyloid deposition in the mouse models or to other factors remains to be determined.