Drug repurposing of rapamycin mitigates amyloid beta associated proteotoxicity in Caenorhabditis elegans

Abstract

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting an estimated 55 million people and projected to exceed 130 million by 2050. Defined neuropathologically by the extracellular accumulation of amyloid-beta (Aβ) peptides and intracellular neurofibrillary tangles of hyperphosphorylated tau, AD currently lacks disease-modifying therapies capable of halting or reversing neurodegeneration. The proteotoxic accumulation of Aβ is a central pathogenic event, and strategies that enhance endogenous clearance mechanisms represent a compelling therapeutic area. Rapamycin (sirolimus), a macrolide allosteric inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1), is one of the most robustly validated pharmacological extenders of lifespan across model organisms and has demonstrated neuroprotective potential in mammalian AD models. Its capacity to provide mTORC1-mediated suppression of autophagy and to reduce neuroinflammation positions it as an attractive drug-repurposing candidate for AD. However, the extent to which rapamycin can mitigate Aβ proteotoxicity in Caenorhabditis elegans remains unexplored, and leveraging this model organism offers a powerful opportunity to study the mechanism by which rapamycin-mediated mTOR inhibition interacts with amyloid-β aggregation, clearance pathways, and proteostasis in the context of Alzheimer's-related neurodegeneration. In this study, we used two well-established transgenic Caenorhabditis elegans models of Aβ proteotoxicity: the muscle-specific temperature-inducible strain CL4176 (Pmyo-3