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PNAS 101 (14): 4752-4757

Copyright © 2004 by the National Academy of Sciences.


Metabolite-initiated protein misfolding may trigger Alzheimer's disease

Qinghai Zhang *, Evan T. Powers *, Jorge Nieva {dagger}, Mary E. Huff *, Maria A. Dendle *, Jan Bieschke *, Charles G. Glabe {ddagger}, Albert Eschenmoser * §, Paul Wentworth, Jr. * ¶, Richard A. Lerner *, and Jeffery W. Kelly * ||

*Department of Chemistry and The Skaggs Institute of Chemical Biology, {dagger}Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; {ddagger}Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; §Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule, Hönggerberg HCI-309, Universitätstrasse, 16 CH-8093 Zürich, Switzerland; and Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom

Contributed by Richard A. Lerner, February 9, 2004

Abstract: Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individuals, covalently modifies the protein or peptide and causes it to misfold, but evidence for this is sparse. Candidate metabolites are suggested by the recently appreciated links between Alzheimer's disease (AD) and atherosclerosis, known chronic inflammatory metabolites, and the newly discovered generation of ozone during inflammation. Here we report detection of cholesterol ozonolysis products in human brains. These products and a related, lipid-derived aldehyde covalently modify A{beta}, dramatically accelerating its amyloidogenesis in vitro, providing a possible chemical link between hypercholesterolemia, inflammation, atherosclerosis, and sporadic AD.

Abbreviations: AD, Alzheimer's disease; A{beta}, amyloid {beta} peptide; AFM, atomic force microscopy; RT, retention time; LC, liquid chromatography; TTR, transthyretin; TfT, thioflavin T.

|| To whom correspondence should be addressed. E-mail: jkelly{at}

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