Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer’s disease (AD), implicating key roles for chromosome 21–encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene–mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted β cleavage of APP and Aβ generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.
Qiuyang Zheng, Beibei Song, Guilin Li, Fang Cai, Meiling Wu, Yingjun Zhao, LuLin Jiang, Tiantian Guo, Mingyu Shen, Huan Hou, Ying Zhou, Yini Zhao, Anjie Di, Lishan Zhang, Fanwei Zeng, Xiu-Fang Zhang, Hong Luo, Xian Zhang, Hongfeng Zhang, Zhiping Zeng, Timothy Y. Huang, Chen Dong, Hong Qing, Yun Zhang, Qing Zhang, Xu Wang, Yili Wu, Huaxi Xu, Weihong Song, Xin Wang
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