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J Biol Chem, Vol. 274, Issue 18, 12619-12625, April 30, 1999

A Molecular Model of Alzheimer Amyloid beta -Peptide Fibril Formation

Lars O. TjernbergDagger , David J. E. Callaway, Agneta Tjernbergparallel , Solveig HahneDagger , Christina LilliehöökDagger , Lars TereniusDagger , Johan Thyberg**, and Christer NordstedtDagger

From the Dagger  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 parallel  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

Polymerization of the amyloid beta (Abeta ) 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 Abeta -fragments containing the Abeta 16-20 sequence, previously shown essential for Abeta -Abeta binding, were incubated in a physiological buffer. Electron microscopy revealed that the shortest fibril-forming sequence was Abeta 14-23. Substitutions in this decapeptide impaired fibril formation and deletion of the decapeptide from Abeta 1-42 inhibited fibril formation completely. All studied peptides that formed fibrils also formed stable dimers and/or tetramers. Molecular modeling of Abeta 14-23 oligomers in an antiparallel beta -sheet conformation displayed favorable hydrophobic interactions stabilized by salt bridges between all charged residues. We propose that this decapeptide sequence forms the core of Abeta -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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