ALZHEIMERS BETA-AMYLOID VASOACTIVITY - IDENTIFICATION OF A NOVEL BETA-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 len gth, timing) suggest that the mechanism is distinct from A beta cytoto xicity, To identify which properties of A beta determine its biologica l activity on vessels, we investigated a number of A beta analogues an d fragments, individually and in combination, including those that are known to be associated with Alzheimer's disease (A beta(1-42)) and he reditary cerebral hemorrhage with amyloidosis - Dutch type (A beta(22Q )(1-40)) The vasoactivity appears to be related to the conformation ad opted 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 r andom coil wild type A beta(1-40) However, the most vasoactive A beta peptides were combinations which contain mixtures of random coil and b eta-sheet structure, The finding that peptides containing low or high levels of beta-pleated conformation are less vasoactive than those con taining intermediate amounts of this structural motif allows us to pro pose the existence of a transitional form between random coil and beta -pleated that is the vasoactive species of A beta, This is the first t ime that A beta conformational intermediates have been identified and a biological activity associated with them. (C) 1998 Federation of Eur opean Biochemical Societies.