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

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 5xFAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5xFAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5xFAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted beta cleavage of APP and A beta generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5xFAD 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.

Automated summary

Down syndrome is one of the critical risk factors for early-onset Alzheimer's disease, and the DS-related gene USP25 has been identified as a critical regulator of AD pathology, potentially serving as a pharmacological target for AD drug development.