Soluble amyloid-β protein (Aβ) oligomers have been recognized to be early and key intermediates in Alzheimer's disease-related synaptic dysfunction. In this study, using in vitro electrophysiology, we investigated interactions of the acidic oligosaccharide sugar chain (AOSC), a marine-derived acidic oligosaccharide, with oligomeric Aβ. We found that the inhibition of long-term potentiation (LTP) induced by Aβ oligomers can be dose dependently reversed by the application of AOSC, whereas AOSC alone did not alter normal LTP induction. Interestingly, treatment with Aβ monomers with or without AOSC did not affect LTP induction. Additionally, when fresh-made Aβ was co-incubated with AOSC before in vitro testing, there was no impairment of LTP induction. The results from Western blots demonstrated that AOSC prevent the aggregation of Aβ oligomers. These findings indicate that AOSC may reverse Aβ oligomer-mediated cytotoxicity by directly disrupting the amyloid oligomer aggregation, and this action is concentration dependent. Thus, we propose that AOSC might be a potential therapeutic drug for Alzheimer's disease due to its protection against oligomeric Aβ-induced dysfunction of synaptic plasticity.