Zheng Qiuyang, Li Guilin, Wang Shihua, Zhou Ying, Liu Ke, Gao Yue, Zhou Yulin, Zheng Liangkai, Zhu Lin, Deng Qingfang, Wu Meiling, Di Anjie, Zhang Lishan, Zhao Yingjun, Zhang Hongfeng, Sun Hao, Dong Chen, Xu Huaxi, Wang Xin
State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China.
Sci Adv. 2021 Jan 1;7(1). doi: 10.1126/sciadv.abe1340. Print 2021 Jan.
Down syndrome (DS), caused by trisomy of chromosome 21, is the most significant risk factor for early-onset Alzheimer's disease (AD); however, underlying mechanisms linking DS and AD remain unclear. Here, we show that triplication of homologous chromosome 21 genes aggravates neuroinflammation in combined murine DS-AD models. Overexpression of , a deubiquitinating enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of reduces neuroinflammation and rescues synaptic and cognitive function in 5×FAD mice. Mechanistically, USP25 deficiency attenuates microglia-mediated proinflammatory cytokine overproduction and synapse elimination. Inhibition of USP25 reestablishes homeostatic microglial signatures and restores synaptic and cognitive function in 5×FAD mice. In summary, we demonstrate an unprecedented role for trisomy 21 and pathogenic effects associated with microgliosis as a result of the increased dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.
唐氏综合征（DS）由21号染色体三体性引起，是早发性阿尔茨海默病（AD）的最重要风险因素；然而，将DS与AD联系起来的潜在机制仍不清楚。在此，我们表明同源21号染色体基因的三倍化会加重联合小鼠DS-AD模型中的神经炎症。由21号染色体编码的去泛素化酶的过表达会导致小胶质细胞活化，并诱导突触和认知缺陷，而对其进行基因敲除则可减轻神经炎症，并挽救5×FAD小鼠的突触和认知功能。从机制上讲，USP25缺陷可减弱小胶质细胞介导的促炎细胞因子过量产生和突触消除。抑制USP25可重建小胶质细胞的稳态特征，并恢复5×FAD小鼠的突触和认知功能。总之，我们证明了21号染色体三体性的前所未有的作用以及由于USP25剂量增加导致的与小胶质细胞增生相关的致病效应，这表明USP25是DS和AD中神经炎症的治疗靶点。
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