Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2)

Abstract

BackgroundTREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined.MethodsPotential binding of oligomeric amyloid-β 1–42 (oAβ1–42) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ1–42 to activate TREM2 signaling pathways was examined by analyzing the phosphorylation of Syk and Akt in primary microglia as well as TREM2-mediated signaling in a reporter cell system. Lastly, the functional outcome of oAβ1–42-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ1–42-bearing brain areas in vivo.ResultsWe found that oAβ1–42 bound to TREM2 with high affinity and activated TREM2-dependent signaling pathway. Neither monomeric nor scrambled Aβ bound to TREM2 supporting a specific interaction between oAβ and TREM2. The disease-associated mutations of TREM2 reduced its binding affinity to oAβ1–42. Furthermore, we identified several positively charged amino acids within residues 31–91 of TREM2 that were crucial for its interaction with oAβ1–42. Importantly, oAβ1–42 promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner.ConclusionsOur data establish a critical link between oAβ1–42, a major pathological component of AD, and TREM2, a strong genetic risk factor for AD expressed in microglia, and suggest that such interaction contributes to the pathogenic events in AD by modulating microglial responses.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0247-7) contains supplementary material, which is available to authorized users.

High‐affinity interactions and signal transduction between Aβ oligomers and TREM 2

“…An interaction between TREM2 and Ab42 oligomers has also recently been reported by several other groups Zhong et al, 2018). Our data and these reports consistently show stronger binding between TREM2 and Ab oligomers compared to monomers .…”

“…However, our data indicate that these functional effects are not attributable to decreased affinity for Aβ under the conditions tested. The functionality of interaction between Aβ oligomers and TREM2 showed an activation of NFAT signaling as observed by Zhong et al (). This signaling activation was indirectly confirmed by showing that Aβ42 oligomers enhanced the interaction between TREM2 and DAP12 and induced SYK phosphorylation, an important factor for NFAT signaling (Zhao et al , ).…”

“…A final and important discrepancy between these reports is that we reproducibly do not detect differences in affinity between various forms of Aβ and TREM2 WT and the AD variants in either the BLI studies or in ELISA assays. Notably, although these other reports use BLI to calculate affinity of TREM2 WT to oligomeric Aβ, only solid‐phase plate binding assays are used to show differences in the affinity between Aβ42 oligomers and TREM2 or the TREM2 variants (Zhao et al , ; Zhong et al , ). Clearly, many factors ranging from binding buffers to protein purity and also form Aβ oligomers can alter affinity measurements.…”

Functional insights from biophysical study of TREM2 interactions with ApoE and Aβ1-42

“…do not grossly impact protein structure or stability but instead likely disrupt interactions with important ligands [15,16]. Several proteins and biological compounds have been demonstrated to bind TREM2 [17], and AD-relevant ligands such as apoptotic cells [18], phospholipids [18,19], low-and high-density lipoprotein [20,21], apolipoprotein E (ApoE) [22], and oligomeric Aβ [23][24][25] have been confirmed to induce TREM2-mediated signaling or phagocytosis. Given the multiple ligands mediating the various functions associated with TREM2, it is important to understand how TREM2 engages each of these ligands at the molecular level.…”

TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

“…As the identification of these variants, a multitude of studies have attempted to elucidate TREM2's role in AD to gain insight into key microglial functions in disease. These studies have largely focused on the role of TREM2 in mediating microglial responses to amyloid plaques, identifying that TREM2 can bind to Aβ peptides (Lessard et al, 2018;Zhao et al, 2018;Zhong et al, 2018) and is required for microglia to accumulate around amyloid plaques (Jay et al, 2015;Ulrich et al, 2014;Wang et al, 2015;Yuan et al, 2016), phagocytose Aβ (Jay, Hirsch, et al, 2017;Jiang et al, 2014;Kleinberger et al, 2014;Melchior et al, 2010;Parhizkar et al, 2019;Wang et al, 2016;Yuan et al, 2016) and engage in Aβ-driven phenotypic changes in mouse models of AD (Jay et al, 2015;Keren-Shaul et al, 2017;Wang et al, 2015). While these may represent important functions of TREM2 in AD, TREM2 variants have now also been associated with risk for developing frontotemporal dementia and Parkinson's disease (Jay, von Saucken, et al, 2017), and are the genetic cause of Nasu Hakola disease (also termed polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL) (Paloneva et al, 2002), a progressive neurodegenerative disease characterized by white matter loss, psychosis, and dementia (Hakola, 1972;Nasu, Tsukahara, & Terayama, 1973).…”