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.
Highlights
Triggering Receptor expressed on Myeloid Cells 2 (TREM2) is an innate immune receptor expressed in microglia
Our data establish a critical link between oligomeric amyloid-β 1–42 (oAβ1–42), a major pathological component of Alzheimer’s disease (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
In the solid phase protein binding assay, we found a specific binding of oAβ1–42 to soluble TREM2 (sTREM2)-Fc with a KD of 86.50 nM, but not to the Fc region alone or sTREM1-Fc (Fig. 1d)
Summary
TREM2 is an innate immune receptor 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. Alzheimer’s disease (AD) is the most common form of dementia with histopathological hallmarks of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain [1, 2]. As the brain resident innate immune cells, microglia constantly survey the microenvironment and become activated in response to pathogenic components that disrupt the homeostasis of the nervous system [5]. The involvement of microglia in AD is further supported by recent genome-wide association and genome sequencing studies showing that rare coding variants in genes highly expressed in microglia as risk factors for late-onset AD [8,9,10,11,12,13,14,15]. Mounting evidence supports a causal role of microglial dysfunction in AD
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