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TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration
TREM2 is a membrane receptor expressed on microglia that plays a pivotal role in the organization and function of these innate immune cell components within the neurodegenerated brain. Whereas TREM2 deletion has been studied extensively in experimental beta-amyloid and Tau-based models of Alzheimer’...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10252191/ https://www.ncbi.nlm.nih.gov/pubmed/37296669 http://dx.doi.org/10.3390/cells12111549 |
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author | Fassler, Michael Benaim, Clara George, Jacob |
author_facet | Fassler, Michael Benaim, Clara George, Jacob |
author_sort | Fassler, Michael |
collection | PubMed |
description | TREM2 is a membrane receptor expressed on microglia that plays a pivotal role in the organization and function of these innate immune cell components within the neurodegenerated brain. Whereas TREM2 deletion has been studied extensively in experimental beta-amyloid and Tau-based models of Alzheimer’s disease, its engagement, and subsequent agonism have not been tested in the context of Tau pathology. Herein, we explored the effects of Ab-T1, an agonistic TREM2 monoclonal antibody on Tau uptake, phosphorylation, seeding, and spreading as well as its therapeutic efficacy in a Tauopathy model. Ab-T1 enhanced the uptake of misfolded Tau to microglia and induced a non-cell autonomous attenuation of spontaneous Tau seeding and phosphorylation in primary neurons from human Tau transgenic mice. Ex vivo, incubation with Ab-T1 led to a significant reduction in the seeding of Tau pathology in the hTau murine organoid brain system. Systemic administration of Ab-T1 resulted in reduced Tau pathology and propagation when hTau was stereotactically injected into the hemispheres of hTau mice. Intraperitoneal treatment with Ab-T1 lead to attenuation of cognitive decline in the hTau mice that was associated with reduced neurodegeneration and synaptic preservation with amelioration of the global neuroinflammatory program. Collectively, these observations show that TREM2 engagement with an agonistic antibody result in reduced Tau burden concomitant with attenuated neurodegeneration ascribed to the education of resident microglia. These results may suggest that despite the opposing results with regard to the effect of TREM2 knockout in experimental Tau-based model systems, receptor engagement and activation by Ab-T1 appears to possess beneficial effects with respect to the various mechanisms mediating Tau-driven neurodegeneration. |
format | Online Article Text |
id | pubmed-10252191 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102521912023-06-10 TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration Fassler, Michael Benaim, Clara George, Jacob Cells Article TREM2 is a membrane receptor expressed on microglia that plays a pivotal role in the organization and function of these innate immune cell components within the neurodegenerated brain. Whereas TREM2 deletion has been studied extensively in experimental beta-amyloid and Tau-based models of Alzheimer’s disease, its engagement, and subsequent agonism have not been tested in the context of Tau pathology. Herein, we explored the effects of Ab-T1, an agonistic TREM2 monoclonal antibody on Tau uptake, phosphorylation, seeding, and spreading as well as its therapeutic efficacy in a Tauopathy model. Ab-T1 enhanced the uptake of misfolded Tau to microglia and induced a non-cell autonomous attenuation of spontaneous Tau seeding and phosphorylation in primary neurons from human Tau transgenic mice. Ex vivo, incubation with Ab-T1 led to a significant reduction in the seeding of Tau pathology in the hTau murine organoid brain system. Systemic administration of Ab-T1 resulted in reduced Tau pathology and propagation when hTau was stereotactically injected into the hemispheres of hTau mice. Intraperitoneal treatment with Ab-T1 lead to attenuation of cognitive decline in the hTau mice that was associated with reduced neurodegeneration and synaptic preservation with amelioration of the global neuroinflammatory program. Collectively, these observations show that TREM2 engagement with an agonistic antibody result in reduced Tau burden concomitant with attenuated neurodegeneration ascribed to the education of resident microglia. These results may suggest that despite the opposing results with regard to the effect of TREM2 knockout in experimental Tau-based model systems, receptor engagement and activation by Ab-T1 appears to possess beneficial effects with respect to the various mechanisms mediating Tau-driven neurodegeneration. MDPI 2023-06-05 /pmc/articles/PMC10252191/ /pubmed/37296669 http://dx.doi.org/10.3390/cells12111549 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Fassler, Michael Benaim, Clara George, Jacob TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration |
title | TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration |
title_full | TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration |
title_fullStr | TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration |
title_full_unstemmed | TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration |
title_short | TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration |
title_sort | trem2 agonism with a monoclonal antibody attenuates tau pathology and neurodegeneration |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10252191/ https://www.ncbi.nlm.nih.gov/pubmed/37296669 http://dx.doi.org/10.3390/cells12111549 |
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