Amyloid β induces pathological symptoms in various neurodegenerative disorders. It is the hallmark of these neurodegenerative disorders, such as Alzheimer's disease, and is reported to induce neurotoxicity leading to neuronal impairment. The continuous development of neurodegenerative disease accompanies pathological changes in amyloid β deposition in the brain. After amyloid β accumulates, the inadequate clearance of amyloid β further accelerates the development of events in the pathological cascade. In eukaryotes, the proteasome is responsible for the degradation of misfolded and damaged proteins to maintain proteostasis. Therefore, screening candidates that preserve proteasomal activity may promote amyloid β homeostasis, which is expected to provide new therapeutic opportunities for these neurodegenerative diseases. Ursolic acid, a natural triterpenoid, has prominent pharmacological antioxidant, anti-inflammatory, neuroprotective, and nontoxic activities. Here, we explored the protective effects of ursolic acid on amyloid β-induced pathological symptoms.This study investigated the therapeutic potential of ursolic acid and its underlying molecular mechanisms using a Caenorhabditis elegans transgenic pathological model.In our study, ursolic acid successfully repressed amyloid β-induced paralysis and hypersensitivity to serotonin in Caenorhabditis elegans. The levels of amyloid β monomers, oligomers, and deposits were decreased after treatment with ursolic acid in transgenic nematodes overexpressing human amyloid β; however, ursolic acid did not affect exogenous transgene transcription and expression levels. Ursolic acid transcriptionally enhanced the ubiquitin-proteasome system and augmented proteasome activity in vivo. However, the proteasome inhibitor MG132 abolished the therapeutic effect of ursolic acid on behavioral paralysis, and Parkinson's disease-related-1 was required for the therapeutic effect of ursolic acid.Our study revealed that ursolic acid prevented amyloid β-induced proteotoxic stress, specifically by reducing the amount of amyloid β and increasing proteasome activity in vivo. Furthermore, the therapeutic effect of ursolic acid on transgenic nematodes expressing amyloid β depended on the increased activity of the proteasome. This work provides an essential supplement to the information on the pharmacological mechanism of ursolic acid.Copyright © 2021 Elsevier B.V. All rights reserved.