USP14 inhibitor IU1 alleviates amyloid-β mediated toxicity in Alzheimer's disease cell and worm models

Abstract

Background: Proteostasis dysfunction plays a central role in Alzheimer's disease (AD), where aberrant accumulation of amyloid precursor protein (APP)-derived peptides, including APP-C99 and amyloid-β (Aβ), contributes to neurotoxicity. Previous work with an APP-C99 neuronal cell model revealed impaired proteasome activity, lysosomal dysfunction, and increased autophagic markers LC3 and p62. Objective: To identify small molecule modulators of proteostasis that reduce Aβ-mediated toxicity and to evaluate their mechanism of action in both cellular and C. elegans models of AD. Methods: We screened a library of small molecule proteostasis modulators in the APP-C99 cell model to identify compounds that reduce Aβ-mediated cell death. Hits were further analyzed for their effects on APP-C99/Aβ clearance, autophagy, and proteasomal function. Neuroprotective effects were validated in an AD C. elegans model. Results: The USP14 deubiquitinase inhibitor IU1 increased cell survival by 40%, reduced APP-C99 and Aβ accumulation, restored proteasomal activity, LC3 and p62 levels to control. IU1 also decreased neuronal loss and improved survival and behavior in AD worms. Notably, autophagy activators, including mTOR inhibitors rapamycin, everolimus, and temsirolimus, worsened Aβ toxicity. Conversely, autophagy inhibitors such as Bafilomycin A and chloroquine reduced APP-C99/Aβ accumulation, enhanced proteasomal activity, decreased cell death, and improved neurodegeneration and behavior in the worm model. Conclusions: This study reveals that, under Aβ-mediated proteostasis dysfunction, autophagy activation exacerbates toxicity, whereas proteasome activation via allosteric inhibition of USP14 using IU1 was neuroprotective. These findings provide evidence to suggest that targeting proteasome stimulation via pharmacological inhibition of USP14 offers a promising therapeutic strategy for AD.

Keywords

Alzheimer’s disease, amyloid precursor protein, amyloid-β protein, autophagy, C. elegans, ubiquitin-proteasome systems

Document Type

Journal Article

Date of Publication

4-1-2026

Volume

110

Issue

3

PubMed ID

41823665

Publication Title

Journal of Alzheimer's Disease

Publisher

Sage

School

Centre of Excellence for Alzheimer's Disease Research and Care / School of Medical and Health Sciences / Sarich and Patricia Neuroscience Research Institute

Funders

National Health and Medical Research Council - Australian Research Council Dementia Research Development Fellowship

Grant Number

NHMRC-ARC Number : APP1107109

Comments

Ariyath, A., Hone, E., Fernando, W. M. a. D. B., Pedrini, S., Martins, R., & Bharadwaj, P. (2026). USP14 inhibitor IU1 alleviates amyloid-β mediated toxicity in Alzheimer’s disease cell and worm models. Journal of Alzheimer’s Disease, 110(3), 1328–1354. https://doi.org/10.1177/13872877261422775

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subscription content

First Page

1328

Last Page

1354

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Link to publisher version (DOI)

10.1177/13872877261422775