Combinations of Vitamin A and Vitamin E Metabolites Confer Resilience against Amyloid-β Aggregation

[Image: see text] Alzheimer’s disease is characterized by the presence in the brain of amyloid plaques formed by the aberrant deposition of the amyloid-β peptide (Aβ). Since many vitamins are dysregulated in this disease, we explored whether these molecules contribute to the protein homeostasis system by modulating Aβ aggregation. By screening 18 fat-soluble and water-soluble vitamin metabolites, we found that retinoic acid and α-tocopherol, two metabolites of vitamin A and vitamin E, respectively, affect Aβ aggregation both in vitro and in a Caenorhabditis elegans model of Aβ toxicity. We then show that the effects of these two vitamin metabolites in specific combinations cancel each other out, consistent with the “resilience in complexity” hypothesis, according to which the complex composition of the cellular environment could have an overall protective role against protein aggregation through the simultaneous presence of aggregation promoters and inhibitors. Taken together, these results indicate that vitamins can be added to the list of components of the protein homeostasis system that regulate protein aggregation.