Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model
Abstract The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non‐canonical translation of the expanded repeat results in abundant poly‐GA inclusion pathology throughout the CNS. (GA)149‐CFP expression in mice trig...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201910919 |
| _version_ | 1797284028655599616 |
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| author | Qihui Zhou Nikola Mareljic Meike Michaelsen Samira Parhizkar Steffanie Heindl Brigitte Nuscher Daniel Farny Mareike Czuppa Carina Schludi Alexander Graf Stefan Krebs Helmut Blum Regina Feederle Stefan Roth Christian Haass Thomas Arzberger Arthur Liesz Dieter Edbauer |
| author_facet | Qihui Zhou Nikola Mareljic Meike Michaelsen Samira Parhizkar Steffanie Heindl Brigitte Nuscher Daniel Farny Mareike Czuppa Carina Schludi Alexander Graf Stefan Krebs Helmut Blum Regina Feederle Stefan Roth Christian Haass Thomas Arzberger Arthur Liesz Dieter Edbauer |
| author_sort | Qihui Zhou |
| collection | DOAJ |
| description | Abstract The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non‐canonical translation of the expanded repeat results in abundant poly‐GA inclusion pathology throughout the CNS. (GA)149‐CFP expression in mice triggers motor deficits and neuroinflammation. Since poly‐GA is transmitted between cells, we investigated the therapeutic potential of anti‐GA antibodies by vaccinating (GA)149‐CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin‐(GA)10 conjugates and pre‐aggregated carrier‐free (GA)15. Only ovalbumin‐(GA)10 immunization induced a strong anti‐GA response. The resulting antisera detected poly‐GA aggregates in cell culture and patient tissue. Ovalbumin‐(GA)10 immunization largely rescued the motor function in (GA)149‐CFP transgenic mice and reduced poly‐GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin‐(GA)10‐immunized poly‐GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP‐43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers. |
| first_indexed | 2024-03-07T17:42:09Z |
| format | Article |
| id | doaj.art-94311c357d894315a7a860a7ca6f1ed6 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:42:09Z |
| publishDate | 2020-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-94311c357d894315a7a860a7ca6f1ed62024-03-02T15:58:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-02-01122n/an/a10.15252/emmm.201910919Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse modelQihui Zhou0Nikola Mareljic1Meike Michaelsen2Samira Parhizkar3Steffanie Heindl4Brigitte Nuscher5Daniel Farny6Mareike Czuppa7Carina Schludi8Alexander Graf9Stefan Krebs10Helmut Blum11Regina Feederle12Stefan Roth13Christian Haass14Thomas Arzberger15Arthur Liesz16Dieter Edbauer17German Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität Munich Munich GermanyInstitute for Stroke and Dementia Research Ludwig‐Maximilians‐University Munich Munich GermanyChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität Munich Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyLaboratory for Functional Genome Analysis Gene Center Ludwig Maximilian University of Munich Munich GermanyLaboratory for Functional Genome Analysis Gene Center Ludwig Maximilian University of Munich Munich GermanyLaboratory for Functional Genome Analysis Gene Center Ludwig Maximilian University of Munich Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyMunich Cluster of Systems Neurology (SyNergy) Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyMunich Cluster of Systems Neurology (SyNergy) Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich Munich GermanyAbstract The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non‐canonical translation of the expanded repeat results in abundant poly‐GA inclusion pathology throughout the CNS. (GA)149‐CFP expression in mice triggers motor deficits and neuroinflammation. Since poly‐GA is transmitted between cells, we investigated the therapeutic potential of anti‐GA antibodies by vaccinating (GA)149‐CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin‐(GA)10 conjugates and pre‐aggregated carrier‐free (GA)15. Only ovalbumin‐(GA)10 immunization induced a strong anti‐GA response. The resulting antisera detected poly‐GA aggregates in cell culture and patient tissue. Ovalbumin‐(GA)10 immunization largely rescued the motor function in (GA)149‐CFP transgenic mice and reduced poly‐GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin‐(GA)10‐immunized poly‐GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP‐43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.https://doi.org/10.15252/emmm.201910919amyotrophic lateral sclerosisC9orf72frontotemporal dementiaimmunotherapyneurodegeneration |
| spellingShingle | Qihui Zhou Nikola Mareljic Meike Michaelsen Samira Parhizkar Steffanie Heindl Brigitte Nuscher Daniel Farny Mareike Czuppa Carina Schludi Alexander Graf Stefan Krebs Helmut Blum Regina Feederle Stefan Roth Christian Haass Thomas Arzberger Arthur Liesz Dieter Edbauer Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model EMBO Molecular Medicine amyotrophic lateral sclerosis C9orf72 frontotemporal dementia immunotherapy neurodegeneration |
| title | Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model |
| title_full | Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model |
| title_fullStr | Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model |
| title_full_unstemmed | Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model |
| title_short | Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model |
| title_sort | active poly ga vaccination prevents microglia activation and motor deficits in a c9orf72 mouse model |
| topic | amyotrophic lateral sclerosis C9orf72 frontotemporal dementia immunotherapy neurodegeneration |
| url | https://doi.org/10.15252/emmm.201910919 |
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