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Zheng, Qiuyang; Song, Beibei; Li, Guilin; Cai, Fang; Wu, Meiling; Zhao, Yingjun; Jiang, LuLin; Guo, Tiantian; Shen, Mingyu; Hou, Huan; Zhou, Ying; Zhao, Yini; Di, Anjie; Zhang, Lishan; Zeng, Fanwei; Zhang, Xiu-Fang; Luo, Hong; Zhang, Xian; Zhang, Hongfeng; Zeng, Zhiping; Huang, Timothy Y; Dong, Chen; Qing, Hong; Zhang, Yun; Zhang, Qing; Wang, Xu; Wu, Yili; Xu, Huaxi; Song, Weihong; Wang, Xin
The Journal of clinical investigation, 03/2022, Letnik: 132, Številka: 5Journal Article
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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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