Amyloid-beta (Aβ1–42)-induced paralysis in Caenorhabditis elegans is reduced by restricted cholesterol supply

Abstract

Alzheimer’ disease is a neurodegenerative disorder characterized by the misfolding and aggregation of amyloid β (Aβ). This process is influenced through supply of cholesterol via apolipoproteins to neurons. In the present study, we used the transgenic Caenorhabditis elegans strain CL2006, which expresses Aβ1–42 under control of a muscle-specific promoter, to test the effects of the apolipoprotein B homologue vitellogenin-6 on paralysis. Knockdown of vitellogenin-6 using RNA-interference (RNAi) recently was shown to significantly reduce cholesterol absorption in C. elegans, and both, RNAi for vitellogenin-6 or lowering the cholesterol concentration in the medium was associated with reduced Aβ-aggregation and paralysis in the nematodes. The effects of both interventions are mediated through the inhibition of the steroidal-signaling pathway since knockdown of its key factors DAF-9 or DAF-12 reduced paralysis independent of the cholesterol concentration and without additive effects by vitellogenin-6 RNAi. Double-RNAi for daf-12 and the downstream target of insulin-signaling, the foxo transcription factor daf-16, revealed that the paralysis-triggering effects of daf-16 RNAi were dominant over the preventive effects of daf-12 RNAi. Identical observations were made when the transcriptional co-activators of DAF-16, ftt-2 or par-5 were knocked down instead of daf-16. In conclusion, interactions between the steroidal and insulin-signaling pathways were identified in Aβ1–42 expressing CL2006, where cholesterol deprivation inhibits steroidal-signaling and thereby activates DAF-16-signaling. Those effects were associated with a reduced Alzheimer phenotype in the nematodes, i.e. reduced protein aggregation and paralysis.