F1‐01‐02: Functional insights into gwas‐derived ad candidate risk factors using RNA interference in C. elegans

beta-amyloid peptide (Abeta) toxicity by transgenic expression of human Abeta42 in the intensely studied nematode worm C. elegans. Induction of Abeta expression in this model leads to a paralysis phenotype with highly reproducible timing. Results: We found that aqueous coffee extracts can dramatically delay the onset of Abeta-induced paralysis in this model. The primary protective component(s) in the coffee extract were not caffeine, although caffeine by itself did show some protection. Coffee exposure did not decrease expression of the Abeta transgene, suggesting that coffee protection was acting by either preventing the formation of a toxic Abeta species or countering a downstream toxic pathway. We hypothesized that the protective compounds in coffee extract might be acting by induction of a previously identified stress response pathway. We therefore used a suite of transgenic GFP reporter strains to test whether coffee extract induced any of the major stress response pathways identified in C. elegans. This screen revealed that coffee extracts specifically activated the skn-1 pathway, which is orthologous to the Nrf2 phase II detoxification pathway of mammals. Inactivation of skn-1 genetically or by RNA interference strongly blocked the protective effects of coffee and caffeine, indicating activation of the skn-1 pathway was the primary mechanism of coffee protection. Coffee also protected against toxicity resulting from an aggregating form of GFP (GFP::degron) in a skn-1-dependent manner. Conclusions: These results suggest that the reported protective effects of coffee in multiple neurodegenerative diseases may result from a general activation of the Nrf2 phase II detoxicification pathway.