Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor of the innate immune system expressed on microglia, macrophages, dendritic cells, and osteoclasts. TREM2 is a member of the immunoglobulin superfamily. Endogenous ligands of this receptor are unknown but when triggered, it signals through the transmembrane adapter protein TYROBP/DAP12 to activate phagocytosis of pathogens and cellular debris. Anti-inflammatory properties of TREM2 have also been described, whereby TREM2 supresses expression and secretion of inflammatory cytokines in macrophages and microglia.
In 2012, functional variants of TREM2 were associated with late-onset Alzheimer’s disease and frontotemporal dementia. The R47H variant in particular was reported to nearly triple the risk of AD, although the exact genetic burden of this and other TREM2 variants requires further research. Autosomal recessive mutations in TREM2 cause Nasu-Hakola disease; this rare genetic disorder of bone abnormalities and progressive dementia is fatal by mid-life.
Preliminary evidence suggests that TREM2 may affect AD pathogenesis via amyloid-related neuroinflammation and via phagocytosis of amyloid and neuronal debris. Of note, however, patients with Nasu-Hakola disease who lack TREM2 develop no plaque pathology. Network analysis of gene expression data in AD-relevant brain regions, including the hippocampus, has identified TREM2 as a regulatory hub that connects to other genes implicated in Alzheimer’s and related diseases. Although the exact pathological mechanisms remain to be worked out, the association of TREM2 and AD underscores the importance of innate immunity and microglial activity in neurodegeneration.
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