| Summary: | High homocysteine (Hcy) levels, mainly caused by vitamin B<sub>12</sub> deficiency, have been reported to induce amyloid-β (Aβ) formation and tau hyperphosphorylation in mouse models of Alzheimer’s disease. However, the relationship between B<sub>12</sub> deficiency and Aβ aggregation is poorly understood, as is the associated mechanism. In the current study, we used the transgenic <i>C. elegans</i> strain GMC101, which expresses human Aβ<sub>1–42</sub> peptides in muscle cells, to investigate the effects of B<sub>12</sub> deficiency on Aβ aggregation–associated paralysis. <i>C. elegans</i> GMC101 was grown on nematode growth medium with or without B<sub>12</sub> supplementation or with 2-<i>O</i>-α-D-glucopyranosyl-L-ascorbic acid (AsA-2G) supplementation. The worms were age-synchronized by hypochlorite bleaching and incubated at 20 °C. After the worms reached the young adult stage, the temperature was increased to 25 °C to induce Aβ production. Worms lacking B<sub>12</sub> supplementation exhibited paralysis faster and more severely than those that received it. Furthermore, supplementing B<sub>12</sub>-deficient growth medium with AsA-2G rescued the paralysis phenotype. However, AsA-2G had no effect on the aggregation of Aβ peptides. Our results indicated that B<sub>12</sub> supplementation lowered Hcy levels and alleviated Aβ toxicity, suggesting that oxidative stress caused by elevated Hcy levels is an important factor in Aβ toxicity.
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