Chondroitin sulfate E (CS-E), which is characterized by oversulfated disaccharide units, has been shown to regulate neuronal adhesion, neurite outgrowth and exert neuroprotective effects. In view of these findings, here we investigated the anti-Alzheimer's disease (AD) activities of CSE by using transgenic Caenorhabditis elegans model of Alzheimer's disease. The behavioral experiments demonstrated that CSE at the concentration of 1 mg/mL significantly delayed the worm paralysis caused by Aβ aggregation as compared with control group. Western blot analysis revealed that the level of small oligomers in the transgenic C. elegans was significantly reduced upon treatment with CSE. The number of Aβ plaque deposits in transgenic worm was significantly decreased. In addition, CSE also protected the worms from oxidative stress and rescued chemotaxis dysfunction in transgenic strain CL2355. Taken together, these data suggested that CSE could protect against Aβ-induced toxicity in C. elegans. These results offer valuable evidence for the future use of CSE in the development of agents for the treatment of AD.