The conformation of Alzheimer's β peptide determines the rate of amyloid formation and its resistance to proteolysis

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Abstract
Amyloid β-peptide (Aβ) 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 Aβ (sAβ) 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 Aβ, and Aβ analogues bearing amino acid substitutions can adopt two major conformational states in solution: (1) an amyloidogenic conformer (Aβac) with a high content of β-sheet and partly resistant to proteases and (2) a non-amyloidogenic conformer (Aβnac) with a random coil conformation and protease-sensitive. The differences in the fibrillogenesis rate and in the protease resistance among the several Aβ 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. Aβnac containing the sequence 1–40, 1–42 or bearing amino acid substitutions (Dutch variant of Aβ) 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 Aβ conformers with distinct abilities to form amyloid may help to explain why Aβ is found in both soluble and fibrillar forms in vivo.

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