Alzheimer's β-amyloid vasoactivity:: identification of a novel β-amyloid conformational intermediate

The beta-amyloid (A beta) peptide has previously been shown to enhance phenylephrine or endothelin-l induced constriction of aortic rings in vitro. The characteristics of A beta vasoactivity (dose, fragment length, timing) suggest that the mechanism is distinct from A beta cytotoxicity, To identify which properties of A beta determine its biological activity on vessels, we investigated a number of A beta analogues and fragments, individually and in combination, including those that are known to be associated with Alzheimer's disease (A beta(1-42)) and hereditary cerebral hemorrhage with amyloidosis - Dutch type (A beta(22Q)(1-40)) The vasoactivity appears to be related to the conformation adopted by the peptide in solution. The beta-pleated sheet rich A beta(1-42) and A beta(22Q)(1-40) were each less vasoactive than the mainly random coil wild type A beta(1-40) However, the most vasoactive A beta peptides were combinations which contain mixtures of random coil and beta-sheet structure, The finding that peptides containing low or high levels of beta-pleated conformation are less vasoactive than those containing intermediate amounts of this structural motif allows us to propose the existence of a transitional form between random coil and beta-pleated that is the vasoactive species of A beta, This is the first time that A beta conformational intermediates have been identified and a biological activity associated with them. (C) 1998 Federation of European Biochemical Societies.