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.

Keywords: Alzheimer's disease; HDL; LDL; Lipoprotein; Microglia; Monocyte; TREM2.

Figure 1. Activation vs. surface expression plots of TREM2 variants stimulated with different ligands reveals functional alterations

(A-E). %GFP+ reporter cells were measured over a range of concentrations, summed to obtain AUC for each variant and subsequently normalized to TREM2-CV AUC. Hypomorphic variants (activation/expression significantly less than TREM2-CV) and hypermorphic variants (activation/expression significantly greater than TREM2-CV) are colored blue and red, respectively. Separate plots are shown for (A) phosphatidylserine, (B) sulfatide, (C) phosphatidylcholine, (D) HDL, and (E) LDL. The mean % difference in activation/expression from TREM2-CV is summarized in (F). Plots show pooled data from 3 independent experiments, with statistical significance p<0.05 calculated by Holm-Sidak's multiple comparisons test.

Figure 2. TREM2 is expressed by human moDCs but not monocytes

(A) Representative histograms are shown for staining with three different monoclonal antibodies against TREM2 - 21E10 (right), 29E3 (left), and 10B11 (left) on day 0 CD14+ monocytes or day 5 moDCs. Gray histogram represents isotype control. Similar results were obtained for three donors. (B) RNA was isolated from these same cell populations for quantitative RT-PCR of TREM2 isoforms and GAPDH. Results are averaged from two donors. (C) Analysis of large microarray datasets for human monocytes, moDCs, and T lymphocytes, showing TREM2, CD20, NCR1, HLA-DRA, and beta-actin. 5%-95% intervals are shown, with outliers plotted individually.