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



TREM2 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.


Potential binding of oligomeric amyloid-? 1-42 (oA?1-42) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oA?1-42 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 oA?1-42-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oA?1-42-bearing brain areas in vivo.


We found that oA?1-42 bound to TREM2 with high affinity and activated TREM2-dependent signaling pathway. Neither monomeric nor scrambled A? bound to TREM2 supporting a specific interaction between oA? and TREM2. The disease-associated mutations of TREM2 reduced its binding affinity to oA?1-42. Furthermore, we identified several positively charged amino acids within residues 31-91 of TREM2 that were crucial for its interaction with oA?1-42. Importantly, oA?1-42 promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner.


Our data establish a critical link between oA?1-42, 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.

PROVIDER: S-EPMC5870375 | BioStudies |

REPOSITORIES: biostudies

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