Design, synthesis, and biophysical properties of a helical Abeta1-42 analog: Inhibition of fibrillogenesis and cytotoxicity.
The aggregation of amyloid beta-peptide (Abeta) into beta-sheet-rich aggregates is a crucial step in the etiology of Alzheimer's disease. Helical forms of Abeta have been suggested to be intermediates in the aggregation process of the peptide in aqueous phase, micelles and membranes. A stable helical Abeta analog would be useful to investigate the role of helical intermediates in fibrillization by Abeta. Here we designed a helical analog by simply cross-linking the Cys residues of A30C, G37C-Abeta1-42 with 1,6-bismaleimidohexane. The analog assumed a weak alpha-helical conformation in model membranes mimicking lipid raft microdomains of neuronal membranes under conditions in which the wild-type Abeta1-42 formed a beta-sheet, indicating the cross-linking locally induced a helical conformation. Furthermore, addition of equimolar helical Abeta analog significantly reduced the amyloid formation and cytotoxicity by Abeta1-42. Thus, our helical Abeta1-42 is not only a model peptide to investigate the role of helical intermediates in fibrillization by Abeta, but also an inhibitor of Abeta-induced cytotoxicity.
Matsuzaki
Katsumi
K
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. katsumim@pharm.kyoto-u.ac.jp
Okada
Takuma
T
Tsukuda
Miho
M
Ikeda
Keisuke
K
Sohma
Youhei
Y
Chiyomori
Yousuke
Y
Taniguchi
Atsuhiko
A
Nakamura
Setsuko
S
Ito
Nui
N
Hayashi
Yoshio
Y
Kiso
Yoshiaki
Y
D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D003432:Cross-Linking Reagents / Q000737:chemistry; D008301:Maleimides / Q000737:chemistry*; D021962:Membrane Microdomains / Q000737:chemistry; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D051381:Rats
D000682:Amyloid; D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D008301:Maleimides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C075594:1,6-bismaleimidohexane