Alzheimer's disease‐associated TREM2 variants exhibit either decreased or increased ligand‐dependent activation

Abstract

INTRODUCTION TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. METHODS We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. RESULTS We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells. DISCUSSION Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.

TREM2, Microglia, and Neurodegenerative Diseases

“…Using an NFAT reporter cell line expressing TREM2, a broad array of phospholipids (PA, phosphatidylinositol, phosphatidylcholine, PG, and PS), as well as glycolipids from cells and myelin (sulfatide, cerebroside, and sphingomyelin) could activate Ca 2+ signaling; furthermore, this effect could be blocked with a TREM2 antibody, suggesting that the ligands may directly activate TREM2 [54,55]. As expected with the physical interaction between TREM2 and lipoproteins, HDL and LDL were also found to activate human TREM2 signaling in an NFAT reporter cell line [50].…”

“…As measured by NFAT reporter assays, PA, PG, PS, PI, sulfatide, HDL, and LDL signaling through TREM2 were also reduced with R47H and R62H mutations [50,54]. TREM2 T96K and D87N mutants led to increased NFAT reporter activity, suggesting a gain-of-function effect of these mutations (Table 2) [50].…”

“…An additional variant of TREM2, R62H (rs143332484), has also been linked to AD [43,49]. [ 5 5 0 _ T D $ D I F F ] TREM2 variants including D87N (rs142232675), T96K (rs2234253), and others may also be linked to AD, but additional genetic studies will be necessary to confirm these results [43,49,50] ( Table 2). …”

“…Unfortunately, patients with NHD usually perish in their 4th to 5th decades of life [67,68]. Recent studies have suggested that heterozygous gene dosage for TREM2 variants that cause NHD in homozygous carriers may confer increased AD risk [43,49,50], and also that rare coding variants of TYROBP may give rise to early-onset AD in an autosomal dominant manner [69].…”

“…Bone marrow cells and blood monocytes express low to undetectable levels of TREM2, although expression can be induced upon differentiation of the former into macrophages or dendritic cells in vitro [50,87,91].…”