State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
J Clin Invest. 2022 Mar 1;132(5). doi: 10.1172/JCI152170.
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.
唐氏综合征（DS），又称 21 三体，是早发性阿尔茨海默病（AD）的关键危险因素之一，表明 21 号染色体编码基因在 AD 的发病机制中起着关键作用。我们之前发现 21 号染色体编码的去泛素化酶 USP25 在调节 AD 大脑中的小胶质细胞稳态方面发挥作用；然而，USP25 是否影响淀粉样蛋白病理学尚不清楚。在这里，通过将 5×FAD AD 和 Dp16 DS 小鼠杂交，我们观察到 21 三体使 5×FAD 大脑中的淀粉样蛋白病理学加重。此外，细菌人工染色体（BAC）转基因介导的 USP25 过表达增加了 5×FAD 小鼠大脑中的淀粉样蛋白沉积，而 Usp25 的基因缺失减少了淀粉样蛋白沉积。此外，我们的结果表明，USP25 通过减少 APP 和 BACE1 的泛素化和溶酶体降解，促进 APP 的β裂解和 Aβ生成。重要的是，USP25 的药理学抑制改善了 5×FAD 小鼠大脑中的淀粉样蛋白病理学。总之，我们确定与 DS 相关的基因 USP25 是 AD 病理的关键调节剂，我们的数据表明 USP25 可以作为 AD 药物开发的潜在药理学靶点。
