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’...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/11/1549 |
| _version_ | 1827739674251100160 |
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| author | Michael Fassler Clara Benaim Jacob George |
| author_facet | Michael Fassler Clara Benaim Jacob George |
| author_sort | Michael Fassler |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T03:09:33Z |
| format | Article |
| id | doaj.art-6630e081c06e4801a984d6c52ea845a7 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T03:09:33Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-6630e081c06e4801a984d6c52ea845a72023-11-18T07:41:33ZengMDPI AGCells2073-44092023-06-011211154910.3390/cells12111549TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and NeurodegenerationMichael Fassler0Clara Benaim1Jacob George2Cognyxx Pharmaceuticals, Tel Aviv Israel and Kaplan Heart Center, Rehovot 6901658, IsraelCognyxx Pharmaceuticals, Tel Aviv Israel and Kaplan Heart Center, Rehovot 6901658, IsraelCognyxx Pharmaceuticals, Tel Aviv Israel and Kaplan Heart Center, Rehovot 6901658, IsraelTREM2 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.https://www.mdpi.com/2073-4409/12/11/1549TREM2tauopathyneurodegenerationneuroinflammationAlzheimer’s |
| spellingShingle | Michael Fassler Clara Benaim Jacob George TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration Cells TREM2 tauopathy neurodegeneration neuroinflammation Alzheimer’s |
| 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 | TREM2 tauopathy neurodegeneration neuroinflammation Alzheimer’s |
| url | https://www.mdpi.com/2073-4409/12/11/1549 |
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