Amyloid beta-protein (Aβ) is involved in the pathogenesis of Alzheimer's disease (AD). Aβ induces free radical production in neuronal cells, leading to oxidative stress and up-regulation of c-Jun N-terminal kinases (JNK), extracellular-signal-regulated kinases (ERK), p38 mitogen-activated protein kinase (MAPK) pathways and pro-apoptotic Bax expression. Sesamin has been shown to have protection to several models of neurodegenerative diseases by its antioxidant and anti-inflammatory properties. In the present study, we examined the neuroprotective effect of a sesamin derivative, 3-bis (3-methoxybenzyl) butane-1,4-diol (BBD) on Aβ1-42 induced cytotoxicity of PC12 cells. Aβ1-42 induced lipid peroxidation, calcium, reactive oxygen species from the PC12 cells. The effect of BBD on these harmful factors and the related signaling pathways were examined by biochemical and western blot assays. The result showed that BBD protected PC12 cells from Aβ1-42 induced cytotoxicity with the increased cell viability and acetylcholine release, and the decreased lactate dehydrogenase, malondialdehyde and calcium release. BBD significantly reduced Aβ-induced JNK, ERK, p38 MAPK pathways and Bax expression in PC12 cells. Therefore the neuroprotective effect of BBD on Aβ-induced cytotoxicity was involved with antioxidant and anti-inflammatory effects. The result would help the development of new CNS drug for protection of AD.