Amyloid-beta peptide (A beta) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A beta has important physiological roles in addition to its pathological roles. We recently demonstrated that A beta 42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A beta 42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A beta 42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A beta 42 on glutamate-induced neurotoxicity. Non-fibrillar A beta 42, but not fibrillar A beta 42, Protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar A beta 42 decreased both neurotoxicity and increases in the intracellular Ca2+ Concentration induced by N-methyl-D-aspartate (NMDA), but not by alpha-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A beta 42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor. (C) 2009 Elsevier Inc. All rights reserved.