Anti-IgLON5 antibodies cause progressive behavioral and neuropathological changes in mice

被引:24
作者
Ni, You [1 ,2 ]
Feng, Yifan [3 ]
Shen, Dingding [1 ,2 ,4 ]
Chen, Ming [3 ]
Zhu, Xiaona [3 ]
Zhou, Qinming [1 ,2 ]
Gao, Yining [1 ,2 ]
Liu, Jun [1 ,2 ]
Zhang, Qi [4 ,5 ,6 ]
Shen, Yuntian [4 ,5 ,6 ]
Peng, Lisheng [7 ]
Zeng, Zike [3 ]
Yin, Dou [1 ,2 ]
Hu, Ji [3 ,4 ,8 ]
Chen, Sheng [1 ,2 ]
机构
[1] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Neurol, Shanghai 200025, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Inst Neurol, Shanghai 200025, Peoples R China
[3] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
[4] Nantong Univ, Co Innovat Ctr Neuroregenerat, Nantong 226019, Peoples R China
[5] Nantong Univ, Key Lab Neuroregenerat Jiangsu, Nantong 226019, Peoples R China
[6] Nantong Univ, Minist Educ, Nantong 226019, Peoples R China
[7] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Neurol, Guangzhou 510630, Peoples R China
[8] Shanghai Mental Hlth Ctr, Shanghai Key Lab Psychot Disorders, Shanghai 200030, Peoples R China
基金
中国国家自然科学基金;
关键词
Anti-IgLON5; disease; Animal model; Neuropathology; Pathogenesis; MEMORY; AUTOANTIBODIES; PATHOLOGY; SLEEP;
D O I
10.1186/s12974-022-02520-z
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页数:18
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