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

Li Zhong, Zongqi Wang, Daxin Wang, Zhe Wang, Yuka A. Martens, Linbei Wu, Ying Xu, Kai Wang, Jianguo Li, Ruizhi Huang, Dan Can, Huaxi Xu, Guojun D Bu, Xiao Fen Chen

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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 (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. Results: We 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. Conclusions: Our 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.

Original languageEnglish (US)
Article number15
JournalMolecular Neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Mar 27 2018

Fingerprint

Myeloid Cells
Amyloid
Alzheimer Disease
Microglia
Cluster Analysis
Aptitude
Surface Plasmon Resonance
Chemotactic Factors
Amyloid Plaques
Immunoprecipitation
Cell Communication
Neurodegenerative Diseases

Keywords

  • Alzheimer's disease
  • microglia
  • migration
  • TREM2
  • β-amyloid

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

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 D; Chen, Xiao Fen.

In: Molecular Neurodegeneration, Vol. 13, No. 1, 15, 27.03.2018.

Research output: Contribution to journalArticle

Zhong, L, Wang, Z, Wang, D, Wang, Z, Martens, YA, Wu, L, Xu, Y, Wang, K, Li, J, Huang, R, Can, D, Xu, H, Bu, GD & Chen, XF 2018, 'Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2)', Molecular Neurodegeneration, vol. 13, no. 1, 15. https://doi.org/10.1186/s13024-018-0247-7
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 D ; Chen, Xiao Fen. / Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). In: Molecular Neurodegeneration. 2018 ; Vol. 13, No. 1.
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abstract = "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 (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. Results: We 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. Conclusions: Our 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.",
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T1 - Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2)

AU - Zhong, Li

AU - Wang, Zongqi

AU - Wang, Daxin

AU - Wang, Zhe

AU - Martens, Yuka A.

AU - Wu, Linbei

AU - Xu, Ying

AU - Wang, Kai

AU - Li, Jianguo

AU - Huang, Ruizhi

AU - Can, Dan

AU - Xu, Huaxi

AU - Bu, Guojun D

AU - Chen, Xiao Fen

PY - 2018/3/27

Y1 - 2018/3/27

N2 - 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 (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. Results: We 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. Conclusions: Our 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.

AB - 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 (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. Results: We 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. Conclusions: Our 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.

KW - Alzheimer's disease

KW - microglia

KW - migration

KW - TREM2

KW - β-amyloid

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