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J Biol Chem, Vol. 275, Issue 3, 1673-1678, January 21, 2000
From The Alzheimer
Controlling Polymerization of
-Amyloid and Prion-derived
Peptides with Synthetic Small Molecule Ligands*
,,,,,,
tne,, and
F. Hoffmann-La Roche AG, Pharma Division,
Preclinical Research, CH-4070 Basel, Switzerland, the
§ Laboratory of Biochemistry and Molecular Pharmacology,
Section of Drug Dependence Research, Department of Clinical
Neuroscience, Karolinska Hospital, S-171 77 Stockholm, Sweden, and the
¶ Department of Clinical Neuroscience, Occupational Therapy, and
Elderly Care Research, Karolinska Institute, KFC Novum plan 4, S-141
86 Huddinge, Sweden
-amyloid peptide (A) and a
fragment of the prion protein have the capacity of forming amyloid-like
fibrils when incubated under physiological conditions in
vitro. Here we show that a small amyloid ligand, RO-47-1816/001,
enhances this process severalfold by binding to amyloid molecules and
apparently promote formation of the peptide-to-peptide bonds that join
the monomers of the amyloid fibrils. This effect could be antagonized by other ligands, including analogues of RO-47-1816/001, as well as the
structurally unrelated ligand Congo red. Analogues of RO-47-1816/001 with low affinity for amyloid did not display any antagonistic effect.
In conclusion, these data suggest that synthetic molecules, and
possibly also small natural substances present in the brain, may act in
a chaperone-like fashion, promoting A polymerization and growth of
amyloid fibrils in vitro and possibly also in
vivo. Furthermore, we demonstrate that small organic molecules
can be used to inhibit the action of amyloid-enhancing compounds.
*
This work was supported by F. Hoffmann-La Roche AG, The
Swedish Medical Research Council, and the Swedish Foundation for
Strategic Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
41-61-688-39-31; Fax: 41-61-688-17-20; E-mail:
christer.nordstedt@roche.com.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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