Anti-IgLON5 antibodies cause progressive behavioral and neuropathological changes in mice
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Published:2022-06-11
Issue:1
Volume:19
Page:
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ISSN:1742-2094
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Container-title:Journal of Neuroinflammation
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language:en
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Short-container-title:J Neuroinflammation
Author:
Ni You, Feng Yifan, Shen Dingding, Chen Ming, Zhu Xiaona, Zhou Qinming, Gao Yining, Liu Jun, Zhang Qi, Shen Yuntian, Peng Lisheng, Zeng Zike, Yin Dou, Hu Ji, Chen ShengORCID
Abstract
Abstract
Background
Anti-IgLON5 disease is a rare neurological disorder associated with autoantibodies against the neuronal cell adhesion protein, IgLON5. Cellular investigations with human IgLON5 antibodies have suggested an antibody-mediated pathogenesis, but whether human IgLON5 autoantibodies can induce disease symptoms in mice is yet to be shown. Moreover, the effects of anti-IgLON5 autoantibodies on neurons and the precise molecular mechanisms in vivo remain controversial.
Methods
We investigated the effects of anti-IgLON5 antibodies in vivo and evaluated their long-term effects. We used two independent passive-transfer animal models and evaluated the effects of the antibodies on mouse behaviors at different time points from day 1 until day 30 after IgG infusion. A wide range of behaviors, including tests of locomotion, coordination, memory, anxiety, depression and social interactions were established. At termination, brain tissue was analyzed for human IgG, neuronal markers, glial markers, synaptic markers and RNA sequencing.
Results
These experiments showed that patient’s anti-IgLON5 antibodies induced progressive and irreversible behavioral deficits in vivo. Notably, cognitive abnormality was supported by impaired average gamma power in the CA1 during novel object recognition testing. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies in the hippocampus of anti-IgLON5 IgG-injected mice, which persisted 30 days after the injection of patient’s antibodies was stopped. Microglial and astrocyte density was increased in the hippocampus of anti-IgLON5 IgG-injected mice at Day 30. Whole-cell voltage clamp recordings proved that anti-IgLON5 antibodies affected synaptic homeostasis. Further western blot investigation of synaptic proteins revealed a reduction of presynaptic (synaptophysin) and post-synaptic (PSD95 and NMDAR1) expression in anti-IgLON5 IgG-injected mice.
Conclusions
Overall, our findings indicated an irreversible effect of anti-IgLON5 antibodies and supported the pathogenicity of these antibodies in vivo.
Funder
Double Hundred Talents Support Program of Shanghai Jiaotong University School of Medicine Shanghai Shuguang Plan Project Shanghai outstanding young scholars Project Clinical Research Plan of SHDC National Natural Science Foundation of China Shanghai talent development project
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology,Immunology,General Neuroscience
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