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J Biol Chem, Vol. 274, Issue 18, 12619-12625, April 30, 1999
From the Polymerization of the amyloid beta (A
A Molecular Model of Alzheimer Amyloid
-Peptide Fibril
Formation
,
,,,,
Laboratory of Biochemistry and Molecular
Pharmacology, Section of Drug Dependence Research, Department of
Clinical Neuroscience, CMM L8:01, Karolinska Hospital, S-171 76 Stockholm, Sweden, the ¶ Picower Institute for Medical Research,
Manhasset, New York 11030, the Mass Spectrometric Section,
Department of Structural Chemistry, Pharmacia & Upjohn, S-112 87 Stockholm, Sweden, and the ** Department of Cell and
Molecular Biology, Medical Nobel Institute, Karolinska Institutet,
S-171 77 Stockholm, Sweden
) peptide
into protease-resistant fibrils is a significant step in the
pathogenesis of Alzheimer's disease. It has not been possible to
obtain detailed structural information about this process with
conventional techniques because the peptide has limited solubility and
does not form crystals. In this work, we present experimental results
leading to a molecular level model for fibril formation. Systematically
selected A-fragments containing the A16-20
sequence, previously shown essential for A-A binding, were incubated in a physiological buffer. Electron microscopy revealed that
the shortest fibril-forming sequence was A14-23.
Substitutions in this decapeptide impaired fibril formation and
deletion of the decapeptide from A1-42 inhibited fibril
formation completely. All studied peptides that formed fibrils also
formed stable dimers and/or tetramers. Molecular modeling of
A14-23 oligomers in an antiparallel -sheet
conformation displayed favorable hydrophobic interactions stabilized by
salt bridges between all charged residues. We propose that this
decapeptide sequence forms the core of A-fibrils, with the
hydrophobic C terminus folding over this core. The identification of
this fundamental sequence and the implied molecular model could
facilitate the design of potential inhibitors of amyloidogenesis.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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