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A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models
Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group US
2023
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9991924/ https://www.ncbi.nlm.nih.gov/pubmed/36635496 http://dx.doi.org/10.1038/s41593-022-01240-0 |
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| author | van Lengerich, Bettina Zhan, Lihong Xia, Dan Chan, Darren Joy, David Park, Joshua I. Tatarakis, David Calvert, Meredith Hummel, Selina Lianoglou, Steve Pizzo, Michelle E. Prorok, Rachel Thomsen, Elliot Bartos, Laura M. Beumers, Philipp Capell, Anja Davis, Sonnet S. de Weerd, Lis Dugas, Jason C. Duque, Joseph Earr, Timothy Gadkar, Kapil Giese, Tina Gill, Audrey Gnörich, Johannes Ha, Connie Kannuswamy, Malavika Kim, Do Jin Kunte, Sebastian T. Kunze, Lea H. Lac, Diana Lechtenberg, Kendra Leung, Amy Wing-Sze Liang, Chun-Chi Lopez, Isabel McQuade, Paul Modi, Anuja Torres, Vanessa O. Nguyen, Hoang N. Pesämaa, Ida Propson, Nicholas Reich, Marvin Robles-Colmenares, Yaneth Schlepckow, Kai Slemann, Luna Solanoy, Hilda Suh, Jung H. Thorne, Robert G. Vieira, Chandler Wind-Mark, Karin Xiong, Ken Zuchero, Y. Joy Yu Diaz, Dolo Dennis, Mark S. Huang, Fen Scearce-Levie, Kimberly Watts, Ryan J. Haass, Christian Lewcock, Joseph W. Di Paolo, Gilbert Brendel, Matthias Sanchez, Pascal E. Monroe, Kathryn M. |
| author_facet | van Lengerich, Bettina Zhan, Lihong Xia, Dan Chan, Darren Joy, David Park, Joshua I. Tatarakis, David Calvert, Meredith Hummel, Selina Lianoglou, Steve Pizzo, Michelle E. Prorok, Rachel Thomsen, Elliot Bartos, Laura M. Beumers, Philipp Capell, Anja Davis, Sonnet S. de Weerd, Lis Dugas, Jason C. Duque, Joseph Earr, Timothy Gadkar, Kapil Giese, Tina Gill, Audrey Gnörich, Johannes Ha, Connie Kannuswamy, Malavika Kim, Do Jin Kunte, Sebastian T. Kunze, Lea H. Lac, Diana Lechtenberg, Kendra Leung, Amy Wing-Sze Liang, Chun-Chi Lopez, Isabel McQuade, Paul Modi, Anuja Torres, Vanessa O. Nguyen, Hoang N. Pesämaa, Ida Propson, Nicholas Reich, Marvin Robles-Colmenares, Yaneth Schlepckow, Kai Slemann, Luna Solanoy, Hilda Suh, Jung H. Thorne, Robert G. Vieira, Chandler Wind-Mark, Karin Xiong, Ken Zuchero, Y. Joy Yu Diaz, Dolo Dennis, Mark S. Huang, Fen Scearce-Levie, Kimberly Watts, Ryan J. Haass, Christian Lewcock, Joseph W. Di Paolo, Gilbert Brendel, Matthias Sanchez, Pascal E. Monroe, Kathryn M. |
| author_sort | van Lengerich, Bettina |
| collection | PubMed |
| description | Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD. |
| format | Online Article Text |
| id | pubmed-9991924 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2023 |
| publisher | Nature Publishing Group US |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-99919242023-03-09 A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models van Lengerich, Bettina Zhan, Lihong Xia, Dan Chan, Darren Joy, David Park, Joshua I. Tatarakis, David Calvert, Meredith Hummel, Selina Lianoglou, Steve Pizzo, Michelle E. Prorok, Rachel Thomsen, Elliot Bartos, Laura M. Beumers, Philipp Capell, Anja Davis, Sonnet S. de Weerd, Lis Dugas, Jason C. Duque, Joseph Earr, Timothy Gadkar, Kapil Giese, Tina Gill, Audrey Gnörich, Johannes Ha, Connie Kannuswamy, Malavika Kim, Do Jin Kunte, Sebastian T. Kunze, Lea H. Lac, Diana Lechtenberg, Kendra Leung, Amy Wing-Sze Liang, Chun-Chi Lopez, Isabel McQuade, Paul Modi, Anuja Torres, Vanessa O. Nguyen, Hoang N. Pesämaa, Ida Propson, Nicholas Reich, Marvin Robles-Colmenares, Yaneth Schlepckow, Kai Slemann, Luna Solanoy, Hilda Suh, Jung H. Thorne, Robert G. Vieira, Chandler Wind-Mark, Karin Xiong, Ken Zuchero, Y. Joy Yu Diaz, Dolo Dennis, Mark S. Huang, Fen Scearce-Levie, Kimberly Watts, Ryan J. Haass, Christian Lewcock, Joseph W. Di Paolo, Gilbert Brendel, Matthias Sanchez, Pascal E. Monroe, Kathryn M. Nat Neurosci Article Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD. Nature Publishing Group US 2023-01-12 2023 /pmc/articles/PMC9991924/ /pubmed/36635496 http://dx.doi.org/10.1038/s41593-022-01240-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
| spellingShingle | Article van Lengerich, Bettina Zhan, Lihong Xia, Dan Chan, Darren Joy, David Park, Joshua I. Tatarakis, David Calvert, Meredith Hummel, Selina Lianoglou, Steve Pizzo, Michelle E. Prorok, Rachel Thomsen, Elliot Bartos, Laura M. Beumers, Philipp Capell, Anja Davis, Sonnet S. de Weerd, Lis Dugas, Jason C. Duque, Joseph Earr, Timothy Gadkar, Kapil Giese, Tina Gill, Audrey Gnörich, Johannes Ha, Connie Kannuswamy, Malavika Kim, Do Jin Kunte, Sebastian T. Kunze, Lea H. Lac, Diana Lechtenberg, Kendra Leung, Amy Wing-Sze Liang, Chun-Chi Lopez, Isabel McQuade, Paul Modi, Anuja Torres, Vanessa O. Nguyen, Hoang N. Pesämaa, Ida Propson, Nicholas Reich, Marvin Robles-Colmenares, Yaneth Schlepckow, Kai Slemann, Luna Solanoy, Hilda Suh, Jung H. Thorne, Robert G. Vieira, Chandler Wind-Mark, Karin Xiong, Ken Zuchero, Y. Joy Yu Diaz, Dolo Dennis, Mark S. Huang, Fen Scearce-Levie, Kimberly Watts, Ryan J. Haass, Christian Lewcock, Joseph W. Di Paolo, Gilbert Brendel, Matthias Sanchez, Pascal E. Monroe, Kathryn M. A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models |
| title | A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models |
| title_full | A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models |
| title_fullStr | A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models |
| title_full_unstemmed | A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models |
| title_short | A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models |
| title_sort | trem2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in alzheimer’s disease models |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9991924/ https://www.ncbi.nlm.nih.gov/pubmed/36635496 http://dx.doi.org/10.1038/s41593-022-01240-0 |
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