TREM2 in Neurodegenerative Diseases

Abstract

TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics. The expression, signaling and function of TREM2 in NDDs have been extensively investigated in an effort to understand the role of immune function in disease pathogenesis and progression. We provide a comprehensive review of our current understanding of TREM2 biology, including new insights into the regulation of TREM2 expression, and TREM2 signaling and function across NDDs. While many open questions remain, the current body of literature provides clarity on several issues. While it is still often cited that TREM2 expression is decreased by pro-inflammatory stimuli, it is now clear that this is true in vitro, but inflammatory stimuli in vivo almost universally increase TREM2 expression. Likewise, while TREM2 function is classically described as promoting an anti-inflammatory phenotype, more than half of published studies demonstrate a pro-inflammatory role for TREM2, suggesting that its role in inflammation is much more complex. Finally, these components of TREM2 biology are applied to a discussion of how TREM2 impacts NDD pathologies and the latest assessment of how these findings might be applied to immune-directed clinical biomarkers and therapeutics.

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

“…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].…”

“…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].…”

“…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.…”