The aggregation of amyloid P-peptide (A beta) into beta-sheet-rich aggregates is a crucial step in the etiology of Alzheimer's disease. Helical forms of A beta have been suggested to be intermediates in the aggregation process of the peptide in aqueous phase, micelles and membranes. A stable helical A beta analog would be useful to investigate the role of helical intermediates in fibrillization by A beta. Here we designed a helical analog by simply cross-linking the Cys residues of A30C, G37C-A beta 1-42 with 1,6-bismaleimidohexane. The analog assumed a weak alpha-helical conformation in model membranes mimicking lipid raft microdomains of neutonal membranes under conditions in which the wild-type A beta 1-42 formed a beta-sheet, indicating the cross-linking locally induced a helical conformation. Furthermore, addition of equimolar helical A beta analog significantly reduced the amyloid formation and cytotoxicity by A beta 1-42. Thus, our helical A beta 1-42 is not only a model pepticle to investigate the role of helical intermediates in fibrillization by AD, but also an inhibitor of A beta-induced cytotoxicity. (c) 2008 Elsevier Inc. All rights reserved.