TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer's disease variant Trem2R47H on murine myeloid cell function

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is an orphan immune receptor expressed on cells of myeloid lineage such as macrophages and microglia. The rare variant R47H TREM2 is associated with an increased risk for Alzheimer's disease, supporting the hypothesis that TREM2 loss of function may exacerbate disease progression. However, a complete knockout of the gene in different genetic models of neurodegenerative diseases has been reported to result in both protective and deleterious effects on disease-related end points and myeloid cell function. Here, we describe a transgenic mouse model and report that even in the absence of additional genetic perturbations, this variant clearly confers a loss of function on myeloid cells. The variant-containing myeloid cells exhibited subtle defects in survival and migration and displayed an unexpected dysregulation of cytokine responses in a lipopolysaccharide challenge environment. These subtle phenotypic defects with a gradation in severity across genotypes were confirmed in whole-genome RNA-Seq analyses of WT,, and myeloid cells under challenge conditions. Of note, TREM2-activating antibodies that boost proximal signaling abrogated survival defects conferred by the variant and also modulated migration and cytokine responses in an antibody-, ligand-, and challenge-dependent manner. In some instances, these antibodies also boosted WT myeloid cell function. Our studies provide a first glimpse into the boost in myeloid cell function that can be achieved by pharmacological modulation of TREM2 activity that can potentially be ameliorative in neurodegenerative diseases such as Alzheimer's disease.

Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

“…This is also consistent with our previous finding demonstrating that inhibition of ADAM proteases is sufficient to increase TREM2-dependent phagocytosis (Kleinberger et al, 2014). Similar findings regarding antibody-mediated survival of macrophages were reported by Cheng et al (2018), although the mechanism of action and in vivo activity of this antibody was not investigated. We now demonstrate that 4D9 exerts its modulating activity via dual mechanisms, first by prevention of shedding and second by agonistic activation of TREM2 receptor signaling.…”

“…Similar findings regarding antibody‐mediated survival of macrophages were reported by Cheng et al (), although the mechanism of action and in vivo activity of this antibody was not investigated. We now demonstrate that 4D9 exerts its modulating activity via dual mechanisms, first by prevention of shedding and second by agonistic activation of TREM2 receptor signaling.…”

TREM2 R47H exacerbates immune response in Alzheimer’s disease brain

“…Studies of the R47H mutation in the murine Trem2 found phenotypes suggesting complete loss of function (42, 43). The variant activated a cryptic splice site in the mouse gene that reduced the levels of the correct transcript and TREM2 protein.…”

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

“…Microglia isolated from TREM2 R47H mice exhibit subtle phenotypic defects that confirm a reduction in some TREM2‐mediated functions. R47H TREM2 knock‐in mice, with no AD genetic background, are healthy and show no clinical phenotype, yet their primary microglia showed reduced survival under colony‐stimulating factor 1‐limiting conditions, decreased motility, and impaired chemotaxis compared with wild‐type mice (Cheng et al, ). Phenotypic defects were similar, but less severe, in R47H TREM2 compared to TREM2 KO primary microglial cells.…”

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMA-COLOGY (Harding et al, 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander, Christopoulos et al, 2017;Alexander, Fabbro et al, 2017a: Alexander, Fabbro et al, 2017b. Zeerleder, 2011Chakradhar, 2016Mastellos et al, 2015 Increase in CR1 would block complement cascade activation Smith, 2002 Factor B, Factor D, Properdin Alternative pathway inhibitors would subtly modulate complement pathway activity and inhibit the amplification arm Katschke et al, 2012Blatt et al, 2016 TREM2-DAP12 signalling TREM2 Activation of TREM2 in R47H TREM2 mice improves myeloid cell survival and migration defects Cheng et al, 2018 SHIP-1 SHIP-1 inhibits TREM2-DAP12-induced signalling Peng et al, 2010 PLC-γ2 Structural data suggest that a point mutation reduces AD risk and may positively modulate enzyme activity Mao et al, 2006;Sims et al, 2017 Apolipoprotein E Activation of TREM2-dependent genes is prevented in APOE KO mice Krasemann et al, 2017 Note: The table summarises possible therapeutic targets involved in the NLRP3 inflammasome activation, the complement system, and TREM2-DAP12 signalling pathways. AD: Alzheimer's disease; CR1: complement receptor 1; TREM2: triggering receptor expressed in myeloid cells 2; SHIP-1: SH-2 containing inositol 5′ polyphosphatase-1; DAP12: DNAX-activation protein 12; KO: knockout.…”