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

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