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
  • 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. [email protected].
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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