The amyloid plaque, consisting of amyloid β-peptide (Aβ) fibrils surrounded by dystrophic neurites, is an invariable feature of Alzheimer's disease. The determination of the molecular structure of Aβ fibrils is a significant goal that may lead to the structure-based design of effective therapeutics for Alzheimer's disease. Technical challenges have thus far rendered this goal impossible. In the present study, we develop an alternative methodology. Rather than determining the structure directly, we design conformationally constrained peptides and demonstrate that only certain ‘bricks’ can aggregate into fibrils morphologically identical to Aβ fibrils. The designed peptides include variants of a decapeptide fragment of Aβ, previously shown to be one of the smallest peptides that (1) includes a pentapeptide sequence necessary for Aβ—Aβ binding and aggregation and (2) can form fibrils indistinguishable from those formed by full-length Aβ. The secondary structure of these bricks is monitored by CD spectroscopy, and electron microscopy is used to study the morphology of the aggregates formed. We then made various residue deletions and substitutions to determine which structural features are essential for fibril formation. From the constraints, statistical analysis of side-chain pair correlations in β-sheets and experimental data, we deduce a detailed model of the peptide strand alignment in fibrils formed by these bricks. Our results show that the constrained decapeptide dimers rapidly form an intramolecular, antiparallel β-sheet and polymerize into amyloid fibrils at low concentrations. We suggest that the formation of an exposed β-sheet (e.g. an Aβ dimer formed by interaction in the decapeptide region) could be a rate-limiting step in fibril formation. A theoretical framework that explains the results is presented in parallel with the data.
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August 2002
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Research Article|
August 15 2002
Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment
Lars O. TJERNBERG;
Lars O. TJERNBERG
∗NEUROTEC, Karolinska Institutet, S141 86 Stockholm, Sweden
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Agneta TJERNBERG;
Agneta TJERNBERG
†Department of Structural Chemistry, Biovitrum, S112 87 Stockholm, Sweden
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Niklas BARK;
Niklas BARK
‡Department of Clinical Neuroscience, CMM L8:01, Karolinska Institutet, S171 76 Stockholm, Sweden
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Yuan SHI;
Yuan SHI
§North Shore/LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030-3849, U.S.A.
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Bela P. RUZSICSKA;
Bela P. RUZSICSKA
§North Shore/LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030-3849, U.S.A.
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Zimei BU;
Zimei BU
∥National Institute of Standards and Technology, 100 Bureau Dr Stop 8562, Gaithersburg, MD 20899-8562, U.S.A.
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Johan THYBERG;
Johan THYBERG
¶Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, S171 77 Stockholm, Sweden
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David J.E. CALLAWAY
David J.E. CALLAWAY
1
§North Shore/LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030-3849, U.S.A.
1To whom correspondence should be addressed (e-mail callaway@indigo.picower.edu).
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Publisher: Portland Press Ltd
Received:
February 06 2002
Revision Received:
May 15 2002
Accepted:
May 22 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 343–351.
Article history
Received:
February 06 2002
Revision Received:
May 15 2002
Accepted:
May 22 2002
Citation
Lars O. TJERNBERG, Agneta TJERNBERG, Niklas BARK, Yuan SHI, Bela P. RUZSICSKA, Zimei BU, Johan THYBERG, David J.E. CALLAWAY; Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment. Biochem J 15 August 2002; 366 (1): 343–351. doi: https://doi.org/10.1042/bj20020229
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