Amyloid beta-peptide (Abeta) and glutamate are generally believed to be closely related to the pathogenesis of Alzheimer's disease and cerebrovascular disease, respectively. Recent advances suggest that risk factors linked to cerebrovascular disease significantly increase the risk of developing Alzheimer's disease. In this study, we examined the effects of pretreatment of cultured hippocampal neurons with Abeta(1-42) (0.3, 0.5, and 1.0microM) for 3h (Abeta preconditioning) on glutamate-induced neurotoxicity. Abeta preconditioning significantly reduced both glutamate-induced neurotoxicity and the glutamate-induced increase in intracellular Ca(2+) concentration ([Ca(2+)](i)). Abeta preconditioning significantly reduced cell surface expression of N-methyl-d-aspartate (NMDA) glutamate receptor subunit protein NR1, although it exerted no significant effect on the total expression of NR1. These results suggest that Abeta preconditioning reduced glutamate-induced neurotoxicity by promoting endocytosis of NMDA receptor, followed by inhibition of the increase in [Ca(2+)](i). Our results support the notion of an association between Alzheimer's disease and cerebrovascular disease, and suggest a new mechanism for neuroprotection by promoting endocytosis of NMDA receptor.