Background and purpose: At the early stage of Alzheimer s Disease (AD), the accumulation of beta-amyloid (A?) oligomers disturbs intracellular Ca2+ homeostasis and disrupts synaptic plasticity of brain neurons. How to prevent A?-induced synaptic failure remains an unsolved obstacle for the therapeutics of AD. In this study, the effects of 2- aminoethoxydiphenyl borate (2-APB), a nonspecific but moderately potent Ca2+ channel inhibitor, on A?-induced deficit of synaptic long-term potentiation (LTP) and the underlying molecular mechanisms were explored. Experimental approach: Electrophysiological recording, membrane protein extraction, hippocampal neuron culture, Western blot assay, and Ca2+ imaging were applied in our study. Key results: 2-APB at the concentration of 10 ?M effectively reversed oligomeric A?1-42 (500 nM) suppression of LTP in hippocampal slices from C57BL/6 wild- type mice. 2-APB also restored AMPA receptor subunit GluR1 phosphorylation and trafficking in A?-treated hippocampal slices, supporting its protective action on synaptic function. A?-mediated abnormal neuronal [Ca2+]i elevation and hyperactivation of BAX, caspase-3,and GSK-3, which are known as mitochondrial apoptotic proteins, were significantlyblocked by 2-APB pretreatment. Moreover, hippocampal LTP deficit in APPswe/PS1?E9gene mutant mice was rescued by 2-APB at 10 ?M. Conclusions and Implications: These data demonstrate that 2-APB is a potentially useful chemical to protect synaptic plasticity against A? neurotoxicity in AD.