Cargando…

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’...

Descripción completa

Detalles Bibliográficos
Autores principales: Fassler, Michael, Benaim, Clara, George, Jacob
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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
_version_ 1785056110925840384
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
work_keys_str_mv AT fasslermichael trem2agonismwithamonoclonalantibodyattenuatestaupathologyandneurodegeneration
AT benaimclara trem2agonismwithamonoclonalantibodyattenuatestaupathologyandneurodegeneration
AT georgejacob trem2agonismwithamonoclonalantibodyattenuatestaupathologyandneurodegeneration