USP25 inhibition ameliorates Alzheimer’s pathology through the regulation of APP processing and Aβ generation
Qiuyang Zheng, … , Weihong Song, Xin Wang
Qiuyang Zheng, … , Weihong Song, Xin Wang
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(5):e152170. https://doi.org/10.1172/JCI152170.
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Research Article Neuroscience

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

Abstract

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.

Authors

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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Figure 2

Usp25 deficiency ameliorates amyloid burden in 5×FAD mice.

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Usp25 deficiency ameliorates amyloid burden in 5×FAD mice. (A) Morris w...
(A) Morris water maze (MWM) test results depicting escape latency, defined as the time taken to find a hidden platform in the 7-day training phase. (B) MWM probe test results. n = 13–19 mice per group. (C) Percentage freezing time in contextual fear conditioning (FC) tests as a readout of associative memory. n = 18 mice per group. Six- to 7-month-old mice were used in behavioral tests. (D-I) Representative immunostaining (D) and quantification of amyloid plaques with a 6E10 antibody (E–G) and thioflavin S (ThioS) (H and I) in the cortices (CTX) and hippocampi (Hipp) in 6-month-old 5×FAD and 5×FAD;Usp25+/– mice. n = 6 mice per group. Scale bar: 50 μm. (J and K) Quantification of soluble Aβ42 (J) and Aβ40 (K) in RIPA buffer in the cortices and hippocampi of 6-month-old 5×FAD and 5×FAD;Usp25+/– mice. n = 10 mice per group. (L–N) Golgi staining (L) and quantification of mature, immature, and total dendritic spines (M) and spine size (N) in the cortical layer V regions of 9-month-old WT, Usp25+/–, 5×FAD, and 5×FAD;Usp25+/– mice. Scale bar: 10 μm. n = 4 mice per group, 22–27 dendrites per group were counted in M, and 95–107 spines per group were counted in N. Data are presented as mean ± SEM (A and E–K) or as median with minimum to maximum bars (B, C, M, and N). P values were determined by 1-way ANOVA with Dunnett’s post hoc analysis in B and C, by the Mann-Whitney test in E–K, by 1-way ANOVA with Tukey’s post hoc analysis in M, and by Kruskal-Wallis test with Dunn’s post hoc analysis in N. *P < 0.05; **P < 0.01; ***P < 0.001; #P < 0.0001.