Vitamin B₁₂ impacts amyloid beta-induced proteotoxicity by regulating the methionine/S-adenosylmethionine cycle

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, complexity of the human diet and indirect effects of the microbiome make it challenging to identify protective nutrients. Multiple factors contribute to AD pathogenesis, including amyloid beta (Aβ) deposition, energy crisis, and oxidative stress. Here, we use Caenorhabditis elegans to define the impact of diet on Aβ proteotoxicity. We discover that dietary vitamin B₁₂ alleviates mitochondrial fragmentation, bioenergetic defects, and oxidative stress, delaying Aβ-induced paralysis without affecting Aβ accumulation. Vitamin B₁₂ has this protective effect by acting as a cofactor for methionine synthase, impacting the methionine/S-adenosylmethionine (SAMe) cycle. Vitamin B₁₂ supplementation of B₁₂-deficient adult Aβ animals is beneficial, demonstrating potential for vitamin B₁₂ as a therapy to target pathogenic features of AD triggered by proteotoxic stress.