Amyloid beta-protein (A beta) is the major constituent of amyloid fibrils composing beta-amyloid plaques and cerebrovascular amyloid in Alzheimer's disease (AD). We studied the effect of metal cations on preformed fibrils of synthetic A beta by Thioflavin T (ThT) fluorescence spectroscopy and electronmicroscopy (EM) in negative staining. The amount of cross beta-pleated sheet structure of A beta 1-40 fibrils was found to decrease by metal cations in a concentration-dependent manner as measured by ThT fluorescence spectroscopy. The order of defibrillization of A beta 1-40 fibrils by metal cations was: Ca2+ and Zn2+ (IC50 = 100 microM) > Mg3+ (IC50 = 300 microM) > Al3+ (IC50 = 1.1 mM). EM analysis in negative staining showed that A beta 1-40 fibrils in the absence of cations were organized in a fine network with a little or no amorphous material. The addition of Ca2+, Mg2+, and Zn2+ to preformed A beta 1-40 fibrils defibrillized the fibrils or converted them into short rods or to amorphous material. Al3+ was less effective, and reduced the fibril network by about 80% of that in the absence of any metal cation. Studies with A beta 1-42 showed that this peptide forms more dense network of fibrils as compared to A beta 1-40. Both ThT fluorescence spectroscopy and EM showed that similar to A beta 1-40, A beta 1-42 fibrils are also defibrillized in the presence of millimolar concentrations of Ca2+. These studies suggest that metal cations can defibrillize the fibrils of synthetic A beta.