The neurotoxicity of aggregated beta-amyloid (Abeta) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD). It can cause neurotoxicity in AD by evoking a cascade of oxidative damage-dependent apoptosis to neurons. In the present study, we for the first time investigated the protective effect of pyrroloquinoline quinone (PQQ), an anionic, water soluble compound that acts as a redox cofactor of bacterial dehydrogenases, on Abeta-induced SH-SY5Y cytotoxicity. Abeta(25-35) significantly reduced cell viability, increased the number of apoptotic-like cells, and increased ROS production. All of these phenotypes induced by Abeta(25-35) were markedly reversed by PQQ. PQQ pretreatment recovered cells from Abeta(25-35)-induced cell death, prevented Abeta(25-35)-induced apoptosis, and decreased ROS production. PQQ strikingly decreased Bax/Bcl-2 ratio, and suppressed the cleavage of caspase-3. These results indicated that PQQ could protect SH-SY5Y cells against beta-amyloid induced neurotoxicity.