The Journal of Clinical Investigation (Mar 2022)

USP25 inhibition ameliorates Alzheimer’s pathology through the regulation of APP processing and Aβ generation

  • 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

Journal volume & issue
Vol. 132, no. 5

Abstract

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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.

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