Examining the Consequences of Altered Insulin Signaling on the Expression of Human Amyloid-Beta in Caenorhabditis elegans
insulin , C.elegans , Alzheimer's Disease , Alzheimer's , Insulin Resistance , Insulin regulation , DAF-2 , DAF-16
Alzheimer’s disease (AD) is a neurodegenerative disease that affects millions of people worldwide. This disease of ageing is the result of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles in the brain, causing symptoms such as confusion, memory loss, and impaired cognitive abilities. It is well known that insulin is a key regulator of the ageing process, as well as many other bodily processes such as metabolism and fat storage. An association between insulin regulation and amyloid-beta plaque accumulation has been noted in Caenorhabditis elegans. This study uses C. elegans to investigate how decreased insulin signaling affects the deposition of human amyloid-beta in a transgenic worm strain that is expressing the human amyloid-beta protein and phenotypes associated with Aβ expression. Expression of human amyloid-beta significantly decreased adult longevity, L1 arrest survival, the number of thrashing/body bends in liquid. A significant increase in the deposition of amyloid protein was found through specific staining. Neuronal ageing was also accelerated relative to wildtype animals. Reduced expression of the insulin receptor (DAF-2) was able to successfully rescue amyloid-beta induced phenotypes: adult longevity, L1 arrest survival, neuronal ageing, and plaque deposition. Overexpression of antagonistic insulins, INS-17 and INS-37 were not able to rescue adult longevity of L1 arrest survival. Antagonistic insulin, INS-39, was able to increase adult longevity but produced no significant rescue of L1 arrest survival. The expression of amyloid beta caused significant neuronal ageing on day 5, day 8 and day 12 of life, with the daf-2 insulin receptor mutant rescuing this phenotype. Other insulin mutants produced differing results at the different time points and showed no consistent results. None of the strains were able to restore the thrashing in liquid deficit of the amyloid-beta worm. These findings indicate the interaction between insulin and Aβ is complex, and research in this area is critical to determine possible therapeutic strategies for AD in the future.