The conformation of Alzheimer's beta peptide determines the rate of amyloid formation and its resistance to proteolysis.
Amyloid beta-peptide (A beta) is found in an aggregated poorly soluble form in senile or neuritic plaques deposited in the brain of individuals affected by Alzheimer's disease (AD). In addition soluble A beta (sA beta) is identified normally circulating in human body fluids. In this study we report that synthetic peptides containing the sequences 1-40 and 1-42 of A beta, and A beta analogues bearing amino acid substitutions can adopt two major conformational states in solution: (1) an amyloidogenic conformer (A beta ac) with a high content of beta-sheet and partly resistant to proteases and (2) a non-amyloidogenic conformer (A beta nac) with a random coil conformation and protease-sensitive. The differences in the fibrillogenesis rate and in the protease resistance among the several A beta peptides studied depend mainly on the relative propensity for adopting the amyloidogenic conformation, which in the absence of external factors is largely conditioned by the primary structure of the peptide. A beta nac containing the sequence 1-40, 1-42 or bearing amino acid substitutions (Dutch variant of A beta) was protease-sensitive and unable to form a significant amount of amyloid even at high concentrations or after long incubations. The finding of the simultaneous existence of different A beta conformers with distinct abilities to form amyloid may help to explain why A beta is found in both soluble and fibrillar forms in vivo.
Soto
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Department of Neurology, New York University Medical Center, NY 10016, U.S.A.
Castaño
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EM
D000544:Alzheimer Disease / Q000378:metabolism*; D000596:Amino Acids / Q000737:chemistry; D000682:Amyloid / Q000096:biosynthesis / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002942:Circular Dichroism; D006868:Hydrolysis; D010446:Peptide Fragments / Q000737:chemistry*
D000596:Amino Acids; D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)