Alzheimer's 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-1 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.
Crawford
F
F
Roskamp Institute, University of South Florida, Tampa 33613, USA. fcrawfor@com1.med.usf.edu
Soto
C
C
Suo
Z
Z
Fang
C
C
Parker
T
T
Sawar
A
A
Frangione
B
B
Mullan
M
M
D016229:Amyloid beta-Peptides / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002942:Circular Dichroism; D019332:Endothelin-1 / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D019332:Endothelin-1; D010446:Peptide Fragments; D014662:Vasoconstrictor Agents