Amyloid beta-peptide (A beta) 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 A beta(1-42) (0.3, 0.5, and 1.0 mu M) for 3 h (A beta preconditioning) on glutamate-induced neurotoxicity. A preconditioning significantly reduced both glutamate-induced neurotoxicity and the glutamate-induced increase in intracellular Ca2+ concentration ([Ca2+](i)). A beta 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 A beta preconditioning reduced glutamate-induced neurotoxicity by promoting endocytosis of NMDA receptor, followed by inhibition of the increase in [Ca2+](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. (c) 2006 Elsevier Inc. All rights reserved.