Resveratrol reduces amyloid-beta (Aß1₋42)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans.

PURPOSE: Resveratrol is a polyphenol present in red wine for which the capability of directly interfering with the hallmark of Alzheimer's disease (AD), i.e. toxic ß-amyloid protein (Aß) aggregation, has been shown recently. Since the stimulation of proteostasis could explain reduced Aß-aggregation, we searched for proteostasis targets of resveratrol. METHODS: The transgenic Caenorhabditis elegans strain CL2006, expressing Aß1-42 under control of a muscle-specific promoter and responding to Aß-toxicity with paralysis, was used as a model. Target identification was accomplished through specific knockdowns of proteostasis genes by RNA interference. Effects of resveratrol on protein aggregation were identified using ProteoStat(®) Detection Reagent, and activation of proteasomal degradation by resveratrol was finally proven using a specific fluorogenic peptide substrate. RESULTS: Resveratrol at a concentration of 100 µM caused a 40 % decrease in paralysis. UBL-5 involved in unfolded protein response (UPR) in mitochondria proved to be necessary for the prevention of Aß-toxicity by resveratrol. Also XBP-1, which represents an endoplasmic reticulum-resident factor involved in UPR, was identified to be necessary for the effects of resveratrol. Regarding protein degradation pathways, the inhibition of macroautophagy and chaperone-mediated autophagy prevented resveratrol from reducing paralysis as did the inhibition of proteasomal degradation. Finally, resveratrol reduced the amount of lysosomes, suggesting increased flux of proteins through the autophagy pathways and activated proteasomal degradation. CONCLUSIONS: Resveratrol reduces the Aß-induced toxicity in a C. elegans model of AD by targeting specific proteins involved in proteostasis and thereby reduces the amount of aggregated Aß.

Amyloid-beta (Aß1₋42)-induced paralysis in Caenorhabditis elegans is inhibited by the polyphenol quercetin through activation of protein degradation pathways.

SCOPE: Dietary polyphenols are suggested to play a role in the prevention of Alzheimer's disease, of which accumulation of aggregated beta amyloid (Aß) is a key histopathological hallmark. We used the transgenic Caenorhabditis elegans strain CL2006, which expresses human Aß1₋42 under control of a muscle-specific promoter and responds to Aß1₋42 aggregation with paralysis, to test effects of the polyphenol quercetin on the phenotype. METHODS AND RESULTS: Quercetin dose-dependently decreased the amount of aggregated proteins in solution and also paralysis in CL2006. The knockdown of key components of unfolded protein response in mitochondria or the endoplasmic reticulum by RNA-interference (RNAi) enhanced paralysis in CL2006 but did not prevent the paralysis reducing activities of quercetin. RNAi for essential members of proteasomal protein degradation or macroautophagy also significantly increased paralysis but prevented quercetin from being effective. Quercetin increased proteasomal activity and, moreover, enhanced the flow of proteins through the macroautophagy pathway as reflected by reduced lysosome staining. CONCLUSION: The proteostasis network, including unfolded protein response, defines the aggregation of Aß1₋42 and the associated paralysis phenotype in a nematode model for Alzheimer's disease. The polyphenol quercetin, by specifically activating macroautophagy and proteasomal degradation pathways, proved able to prevent Aß1₋42 agregation and paralysis.