2. Academic Validation
  3. Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25

Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25

  • Sci Adv. 2021 Jan 1;7(1):eabe1340. doi: 10.1126/sciadv.abe1340.
Qiuyang Zheng 1,  Guilin Li 1,  Shihua Wang 1 2,  Ying Zhou 3,  Ke Liu 3,  Yue Gao 1,  Yulin Zhou 4,  Liangkai Zheng 4,  Lin Zhu 1,  Qingfang Deng 1,  Meiling Wu 1,  Anjie Di 1,  Lishan Zhang 1,  Yingjun Zhao 1,  Hongfeng Zhang 1,  Hao Sun 1,  Chen Dong 5,  Huaxi Xu 1 6,  Xin Wang 7
Affiliations

Affiliations

  • 1 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.
  • 2 School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China.
  • 3 Department of Translational Medicine, School of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
  • 4 Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian 361003, China.
  • 5 Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China.
  • 6 Center for Brain Sciences, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361003, China.
  • 7 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. wangx@xmu.edu.cn.
PMID: 33523861 DOI: 10.1126/sciadv.abe1340
Abstract

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 USP25, a deubiquitinating Enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of Usp25 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 USP25 dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.

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