[
International Worm Meeting,
2021]
Alzheimer's Disease (AD), the most common cause of dementia, is a multifactorial neurodegenerative disorder characterized by accumulation of amyloid-beta (Abeta) plaques, hyperphosphorylated tau, oxidative stress, and mitochondrial dysfunction. Some AD risk factors including genetic predisposition and aging cannot be changed, but diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, it is challenging to determine which individual nutrients are neuroprotective in humans due to organismal complexity, genetic diversity, consumption of complex diets, and indirect dietary effects of gut microbiota. C. elegans eat a simple diet of E. coli and have been used extensively to identify and characterize factors that influence Abeta toxicity. Transgenic expression of toxic human Abeta in C. elegans body wall muscles generates robust time-dependent paralysis as well as AD-like pathological features including defects in mitochondrial function and morphology. We discovered that Abeta-expressing C. elegans fed OP50 E. coli exhibited faster paralysis, lower ATP levels, more mitochondrial fragmentation, and increased reactive oxygen species compared to those raised on HB101 E. coli. This was not due to differences in macronutrient content, but rather on the availability of vitamin B12. We found the B12 supplementation alleviated mitochondrial fragmentation, bioenergetic defects, and oxidative stress, delaying Abeta-induced paralysis without affecting Abeta accumulation in animals fed OP50. Vitamin B12 did not have an additive effect on animals raised on HB101 indicating that supplementation was only beneficial for animals with mild B12 deficiency. Vitamin B12 is an essential cofactor for methionine synthase (METR-1) and methylmalonyl coenzyme A (CoA) mutase (MMCM-1). We discovered that the protective effects of vitamin B12 required METR-1, suggesting that B12 is functioning as an enzyme cofactor rather than as an antioxidant. Methionine supplementation also eliminated the dietary shift in paralysis, consistent with our model in which the amount of vitamin B12 dependent methionine synthase activity impacts Abeta proteotoxicity. Introducing vitamin B12 at adulthood was beneficial for B12 deficient Abeta animals. In conclusion, our results demonstrate the potential for vitamin B12 as a therapy to target pathogenic features of AD triggered by both aging and proteotoxic stress.