Downregulation of USP9X in the DG Region of the Hippocampus Leads to AD-Like Cognitive Dysfunction in Mice.

Abstract

OBJECTIVE: This study investigates the link between ubiquitin-specific peptidase 9 X-linked (USP9X) and Alzheimer's disease (AD) pathogenesis, aiming to identify potential targets for AD diagnosis, treatment, and drug development. METHODS: We constructed a USP9X-inhibited expression mouse model and assessed cognitive and memory functions. We also measured Tau phosphorylation and APP levels in the hippocampal dentate gyrus (DG) and analyzed neuronal functions, dendritic spine features, late apoptosis, and autophagy. RESULTS: Mice with USP9Xinhibition exhibited impaired cognitive and memory functions. An increase in the APP levels and Tau hyperphosphorylation in the DG resembled AD-like pathology. Neurons exhibited abnormal functions, altered dendritic spine morphology, increase in neuronal apoptosis, and dysfunctions, similar to neuron loss observed in AD. CONCLUSION: Investigating the role of USP9X in AD could provide valuable insights for developing novel diagnostic and therapeutic strategies for AD.