Metal cations defibrillize the amyloid beta-protein fibrils.
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.
Chauhan
V P
VP
New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314-6399, USA.
Ray
I
I
Chauhan
A
A
Wegiel
J
J
Wisniewski
H M
HM
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008670:Metals / Q000494:pharmacology*; D010446:Peptide Fragments / Q000187:drug effects; D012995:Solubility
D016229:Amyloid beta-Peptides; D008670:Metals; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)