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Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2)
BACKGROUND: 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 amylo...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870375/ https://www.ncbi.nlm.nih.gov/pubmed/29587871 http://dx.doi.org/10.1186/s13024-018-0247-7 |
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author | Zhong, Li Wang, Zongqi Wang, Daxin Wang, Zhe Martens, Yuka A. Wu, Linbei Xu, Ying Wang, Kai Li, Jianguo Huang, Ruizhi Can, Dan Xu, Huaxi Bu, Guojun Chen, Xiao-Fen |
author_facet | Zhong, Li Wang, Zongqi Wang, Daxin Wang, Zhe Martens, Yuka A. Wu, Linbei Xu, Ying Wang, Kai Li, Jianguo Huang, Ruizhi Can, Dan Xu, Huaxi Bu, Guojun Chen, Xiao-Fen |
author_sort | Zhong, Li |
collection | PubMed |
description | BACKGROUND: 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. METHODS: Potential binding of oligomeric amyloid-β 1–42 (oAβ(1–42)) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ(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 oAβ(1–42)-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ(1–42)-bearing brain areas in vivo. RESULTS: We found that oAβ(1–42) 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 oAβ(1–42). Furthermore, we identified several positively charged amino acids within residues 31–91 of TREM2 that were crucial for its interaction with oAβ(1–42). Importantly, oAβ(1–42) promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner. CONCLUSIONS: Our data establish a critical link between oAβ(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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0247-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5870375 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-58703752018-03-29 Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) Zhong, Li Wang, Zongqi Wang, Daxin Wang, Zhe Martens, Yuka A. Wu, Linbei Xu, Ying Wang, Kai Li, Jianguo Huang, Ruizhi Can, Dan Xu, Huaxi Bu, Guojun Chen, Xiao-Fen Mol Neurodegener Research Article BACKGROUND: 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. METHODS: Potential binding of oligomeric amyloid-β 1–42 (oAβ(1–42)) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ(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 oAβ(1–42)-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ(1–42)-bearing brain areas in vivo. RESULTS: We found that oAβ(1–42) 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 oAβ(1–42). Furthermore, we identified several positively charged amino acids within residues 31–91 of TREM2 that were crucial for its interaction with oAβ(1–42). Importantly, oAβ(1–42) promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner. CONCLUSIONS: Our data establish a critical link between oAβ(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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0247-7) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-27 /pmc/articles/PMC5870375/ /pubmed/29587871 http://dx.doi.org/10.1186/s13024-018-0247-7 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Zhong, Li Wang, Zongqi Wang, Daxin Wang, Zhe Martens, Yuka A. Wu, Linbei Xu, Ying Wang, Kai Li, Jianguo Huang, Ruizhi Can, Dan Xu, Huaxi Bu, Guojun Chen, Xiao-Fen Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) |
title | Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) |
title_full | Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) |
title_fullStr | Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) |
title_full_unstemmed | Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) |
title_short | Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) |
title_sort | amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (trem2) |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870375/ https://www.ncbi.nlm.nih.gov/pubmed/29587871 http://dx.doi.org/10.1186/s13024-018-0247-7 |
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