An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function

Abstract

Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)‐like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2‐dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of TREM2. TREM2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C‐terminal to histidine 157, a position where an AD‐associated coding variant has been discovered (p.H157Y) in the Han Chinese population. Opposite to the characterized mutations within the Ig‐like domain, such as p.T66M and p.Y38C, the p.H157Y variant within the stalk region leads to enhanced shedding of TREM2. Elevated ectodomain shedding reduces cell surface full‐length TREM2 and lowers TREM2‐dependent phagocytosis. Therefore, two seemingly opposite cellular effects of TREM2 variants, namely reduced versus enhanced shedding, result in similar phenotypic outcomes by reducing cell surface TREM2.

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

“…We observed a significantly increased uptake of pHrodo‐labeled Escherichia coli ( E. coli ) in PGRN‐deficient BV2 cells compared to wt (Fig A). Enhanced uptake of pHrodo‐labeled bacteria is in strong contrast to the reduced uptake detected in Trem2 loss‐of‐function mutations (Fig EV1A; Kleinberger et al , , ; Schlepckow et al , ), thus demonstrating that differentially regulated mRNA signatures translate into opposite phagocytic phenotypes. In acutely isolated microglia, uptake of bacteria was also reduced upon loss of TREM2 (Fig EV1B).…”

“…TREM2 is produced as a membrane‐bound type‐1 protein (Kleinberger et al , ), which traffics to the cell surface where it mediates signaling via binding to its co‐receptor, the DNAX activation protein of 12 kDa (DAP12; Ulrich & Holtzman, ; Yeh et al , ). Signaling is terminated by proteolytic shedding of the TREM2 ectodomain (Kleinberger et al , ; Schlepckow et al , ). Several sequence variants associated with TREM2 cause neurodegeneration via a loss of function (Kleinberger et al , , ; Schlepckow et al , ; Ulland et al , ; Song et al , ).…”

“…Signaling is terminated by proteolytic shedding of the TREM2 ectodomain (Kleinberger et al , ; Schlepckow et al , ). Several sequence variants associated with TREM2 cause neurodegeneration via a loss of function (Kleinberger et al , , ; Schlepckow et al , ; Ulland et al , ; Song et al , ). Sequence variants of TREM2 affect a multitude of functions including chemotaxis, migration, survival, binding of phospholipids and ApoE, proliferation, survival, and others (Kleinberger et al , , ; Atagi et al , ; Bailey et al , ; Wang et al , ; Yeh et al , ; Mazaheri et al , ; Ulland et al , ).…”

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

“…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]. Although not much is known about the pathophysiological significance of sTREM2 in comparison with TREM2, recent studies demonstrated several novel aspects of sTREM2, which are reviewed in the next section.…”

“…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]. Therefore, TREM2-related microglial dysfunction can potentially lead to the impairment of brain homeostasis including amyloid-β clearance, possibly leading to neuronal injury and cognitive dysfunction.…”