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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
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.
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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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