Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation
Abstract Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-020-00948-z |
| _version_ | 1818109525965668352 |
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| author | Monika Zilkova Anna Nolle Branislav Kovacech Eva Kontsekova Petronela Weisova Peter Filipcik Rostislav Skrabana Michal Prcina Tomas Hromadka Ondrej Cehlar Gabriela Paulikova Rolkova Denisa Maderova Michal Novak Norbert Zilka Jeroen J. M. Hoozemans |
| author_facet | Monika Zilkova Anna Nolle Branislav Kovacech Eva Kontsekova Petronela Weisova Peter Filipcik Rostislav Skrabana Michal Prcina Tomas Hromadka Ondrej Cehlar Gabriela Paulikova Rolkova Denisa Maderova Michal Novak Norbert Zilka Jeroen J. M. Hoozemans |
| author_sort | Monika Zilkova |
| collection | DOAJ |
| description | Abstract Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro. Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies. The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development. |
| first_indexed | 2024-12-11T02:32:39Z |
| format | Article |
| id | doaj.art-a4c9386438824459a38b0c854273aacf |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-11T02:32:39Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-a4c9386438824459a38b0c854273aacf2022-12-22T01:23:49ZengBMCActa Neuropathologica Communications2051-59602020-05-018111910.1186/s40478-020-00948-zHumanized tau antibodies promote tau uptake by human microglia without any increase of inflammationMonika Zilkova0Anna Nolle1Branislav Kovacech2Eva Kontsekova3Petronela Weisova4Peter Filipcik5Rostislav Skrabana6Michal Prcina7Tomas Hromadka8Ondrej Cehlar9Gabriela Paulikova Rolkova10Denisa Maderova11Michal Novak12Norbert Zilka13Jeroen J. M. Hoozemans14Axon Neuroscience R&D Services SEAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Amsterdam NeuroscienceAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience R&D Services SEAxon Neuroscience SEAxon Neuroscience R&D Services SEAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Amsterdam NeuroscienceAbstract Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro. Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies. The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development.http://link.springer.com/article/10.1186/s40478-020-00948-zTau immunotherapyHumanized antibodyHuman microgliaTau uptake |
| spellingShingle | Monika Zilkova Anna Nolle Branislav Kovacech Eva Kontsekova Petronela Weisova Peter Filipcik Rostislav Skrabana Michal Prcina Tomas Hromadka Ondrej Cehlar Gabriela Paulikova Rolkova Denisa Maderova Michal Novak Norbert Zilka Jeroen J. M. Hoozemans Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation Acta Neuropathologica Communications Tau immunotherapy Humanized antibody Human microglia Tau uptake |
| title | Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation |
| title_full | Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation |
| title_fullStr | Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation |
| title_full_unstemmed | Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation |
| title_short | Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation |
| title_sort | humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation |
| topic | Tau immunotherapy Humanized antibody Human microglia Tau uptake |
| url | http://link.springer.com/article/10.1186/s40478-020-00948-z |
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