TREM2, Microglia, and Neurodegenerative Diseases

A Novel TREM2-Mediated Link between Diabetes and Cognitive Impairment: Recent Findings and Future Perspectives

“…TREM2 is exclusively expressed on myeloid lineage cells including dendritic cells, tissue macrophages, osteoclasts, and microglia [11,12]. Many potential ligands for TREM2 have been proposed, which are characterized based on the type of anionic and/or lipidic species, such as bacterial components, mammalian cellular membrane components and lipoproteins [15].…”

“…TREM2 interacts with the adaptor protein DNAX-activating protein 12 (DAP12)/TYRO protein kinase binding protein (TYROBP) via its transmembrane domain. Following binding to its ligands, TREM2 facilitates DAP12 phosphorylation on tyrosine residues within its immunoreceptor tyrosine-based activation motif region, thereby mediating downstream signaling that leads to various cellular functions including survival, phagocytosis and inflammation [10][11][12]16]. One remarkable characteristic of TREM2 is the release of its soluble ectodomain fragment, soluble TREM2 (sTREM2), into the extracellular space via proteolytic cleavage at the site in the juxtamembrane region by shaddases such as a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) [17][18][19][20].…”

“…Accordingly, recent studies reporting that the R47H TREM2 mutation was associated with an approximately 3-fold increase in AD risk in humans [9][10][11][12] had a deep impact and ripple effect based on the possibility that TREM2 and TREM2-expressing microglia might be novel key targets for elucidating mechanisms underlying AD pathogenesis. Recent accumulating evidence reveals an association between a diverse array of TREM2 variants and risk for AD and other neurodegenerative diseases [10][11][12].…”

“…Accordingly, recent studies reporting that the R47H TREM2 mutation was associated with an approximately 3-fold increase in AD risk in humans [9][10][11][12] had a deep impact and ripple effect based on the possibility that TREM2 and TREM2-expressing microglia might be novel key targets for elucidating mechanisms underlying AD pathogenesis. Recent accumulating evidence reveals an association between a diverse array of TREM2 variants and risk for AD and other neurodegenerative diseases [10][11][12]. These variants include mutations affecting TREM2 structure/function such as the generation of a truncated protein (W44X or W78X variants) [21], inability to associate with its intracellular adaptor, DAP12/TYROBP (K186N variant) [21], reduction in ligand binding ability (R47H variant) [22][23][24], alteration of subcellular localization (reduction on cell surface and increase in endoplasmic reticulum in T66M or Y38C variants) [18,25] and accelerated proteolytic loss from the cell surface (H157Y variant) [19,20].…”

“…Genome-wide association studies recently revealed novel significant associations between variants of the gene triggering receptor expressed on myeloid cell 2 (TREM2) and a high risk for AD and other neurodegenerative diseases [9][10][11][12]. Following these initial observations, an exponentially growing number of basic and clinical studies have focused on the pathological roles of TREM2 in the development and progression of dementia.…”