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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.
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1 Chinese Academy of Sciences, State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Science, School of Chemistry and Chemical Engineering, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419)
2 Chinese Academy of Sciences, State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309); Chinese Academy of Sciences, Innovation Academy for Green Manufacture Institute, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309)
3 Chinese Academy of Sciences, State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309)
4 Chinese Academy of Sciences, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309)