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Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding b...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136959/ https://www.ncbi.nlm.nih.gov/pubmed/32154671 http://dx.doi.org/10.15252/emmm.201911227 |
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author | Schlepckow, Kai Monroe, Kathryn M Kleinberger, Gernot Cantuti‐Castelvetri, Ludovico Parhizkar, Samira Xia, Dan Willem, Michael Werner, Georg Pettkus, Nadine Brunner, Bettina Sülzen, Alice Nuscher, Brigitte Hampel, Heike Xiang, Xianyuan Feederle, Regina Tahirovic, Sabina Park, Joshua I Prorok, Rachel Mahon, Cathal Liang, Chun‐Chi Shi, Ju Kim, Do Jin Sabelström, Hanna Huang, Fen Di Paolo, Gilbert Simons, Mikael Lewcock, Joseph W Haass, Christian |
author_facet | Schlepckow, Kai Monroe, Kathryn M Kleinberger, Gernot Cantuti‐Castelvetri, Ludovico Parhizkar, Samira Xia, Dan Willem, Michael Werner, Georg Pettkus, Nadine Brunner, Bettina Sülzen, Alice Nuscher, Brigitte Hampel, Heike Xiang, Xianyuan Feederle, Regina Tahirovic, Sabina Park, Joshua I Prorok, Rachel Mahon, Cathal Liang, Chun‐Chi Shi, Ju Kim, Do Jin Sabelström, Hanna Huang, Fen Di Paolo, Gilbert Simons, Mikael Lewcock, Joseph W Haass, Christian |
author_sort | Schlepckow, Kai |
collection | PubMed |
description | Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state. |
format | Online Article Text |
id | pubmed-7136959 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71369592020-04-08 Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region Schlepckow, Kai Monroe, Kathryn M Kleinberger, Gernot Cantuti‐Castelvetri, Ludovico Parhizkar, Samira Xia, Dan Willem, Michael Werner, Georg Pettkus, Nadine Brunner, Bettina Sülzen, Alice Nuscher, Brigitte Hampel, Heike Xiang, Xianyuan Feederle, Regina Tahirovic, Sabina Park, Joshua I Prorok, Rachel Mahon, Cathal Liang, Chun‐Chi Shi, Ju Kim, Do Jin Sabelström, Hanna Huang, Fen Di Paolo, Gilbert Simons, Mikael Lewcock, Joseph W Haass, Christian EMBO Mol Med Articles Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state. John Wiley and Sons Inc. 2020-03-10 2020-04-07 /pmc/articles/PMC7136959/ /pubmed/32154671 http://dx.doi.org/10.15252/emmm.201911227 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Schlepckow, Kai Monroe, Kathryn M Kleinberger, Gernot Cantuti‐Castelvetri, Ludovico Parhizkar, Samira Xia, Dan Willem, Michael Werner, Georg Pettkus, Nadine Brunner, Bettina Sülzen, Alice Nuscher, Brigitte Hampel, Heike Xiang, Xianyuan Feederle, Regina Tahirovic, Sabina Park, Joshua I Prorok, Rachel Mahon, Cathal Liang, Chun‐Chi Shi, Ju Kim, Do Jin Sabelström, Hanna Huang, Fen Di Paolo, Gilbert Simons, Mikael Lewcock, Joseph W Haass, Christian Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region |
title | Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region |
title_full | Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region |
title_fullStr | Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region |
title_full_unstemmed | Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region |
title_short | Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region |
title_sort | enhancing protective microglial activities with a dual function trem2 antibody to the stalk region |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136959/ https://www.ncbi.nlm.nih.gov/pubmed/32154671 http://dx.doi.org/10.15252/emmm.201911227 |
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