Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model
Abstract Passive immunotherapy is one of the most promising interventions for Alzheimer’s disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-01-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-022-01273-8 |
| _version_ | 1811175719129055232 |
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| author | Xiao-ying Sun Xiao-lin Yu Jie Zhu Ling-jie Li Lun Zhang Ya-ru Huang Dong-qun Liu Mei Ji Xun Sun Ling-xiao Zhang Wei-wei Zhou Dongming Zhang Jianwei Jiao Rui-tian Liu |
| author_facet | Xiao-ying Sun Xiao-lin Yu Jie Zhu Ling-jie Li Lun Zhang Ya-ru Huang Dong-qun Liu Mei Ji Xun Sun Ling-xiao Zhang Wei-wei Zhou Dongming Zhang Jianwei Jiao Rui-tian Liu |
| author_sort | Xiao-ying Sun |
| collection | DOAJ |
| description | Abstract Passive immunotherapy is one of the most promising interventions for Alzheimer’s disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that Aβ-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aβ, antibody, and complement. Notably, anti-Aβ antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aβ-targeting antibodies, but not their Fab fragments, significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment, whereas the memory impairments in mice were gradually rescued thereafter. Since the recovery rate of synapses in humans is much lower than that in mice, our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies. Therefore, Aβ-targeting antibodies lack of Fc fragment, or with reduced Fc effector function, may not induce microglial synaptic pruning, providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD. |
| first_indexed | 2024-04-10T19:40:21Z |
| format | Article |
| id | doaj.art-e1dfffcdcd3a499c9362a619cc60c54a |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-10T19:40:21Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-e1dfffcdcd3a499c9362a619cc60c54a2023-01-29T12:22:49ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-01-018111410.1038/s41392-022-01273-8Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse modelXiao-ying Sun0Xiao-lin Yu1Jie Zhu2Ling-jie Li3Lun Zhang4Ya-ru Huang5Dong-qun Liu6Mei Ji7Xun Sun8Ling-xiao Zhang9Wei-wei Zhou10Dongming Zhang11Jianwei Jiao12Rui-tian Liu13State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of SciencesAbstract Passive immunotherapy is one of the most promising interventions for Alzheimer’s disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that Aβ-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aβ, antibody, and complement. Notably, anti-Aβ antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aβ-targeting antibodies, but not their Fab fragments, significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment, whereas the memory impairments in mice were gradually rescued thereafter. Since the recovery rate of synapses in humans is much lower than that in mice, our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies. Therefore, Aβ-targeting antibodies lack of Fc fragment, or with reduced Fc effector function, may not induce microglial synaptic pruning, providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.https://doi.org/10.1038/s41392-022-01273-8 |
| spellingShingle | Xiao-ying Sun Xiao-lin Yu Jie Zhu Ling-jie Li Lun Zhang Ya-ru Huang Dong-qun Liu Mei Ji Xun Sun Ling-xiao Zhang Wei-wei Zhou Dongming Zhang Jianwei Jiao Rui-tian Liu Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model Signal Transduction and Targeted Therapy |
| title | Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model |
| title_full | Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model |
| title_fullStr | Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model |
| title_full_unstemmed | Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model |
| title_short | Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model |
| title_sort | fc effector of anti aβ antibody induces synapse loss and cognitive deficits in alzheimer s disease like mouse model |
| url | https://doi.org/10.1038/s41392-022-01273-8 |
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