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J. Biol. Chem., Vol. 282, Issue 13, 9335-9345, March 30, 2007

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Membrane-mediated Amyloidogenesis and the Promotion of Oxidative Lipid Damage by Amyloid Proteins^*

Ian V. J. Murray, Liu Liu, Hiroaki Komatsu, Kunihiro Uryu, Gang Xiao^¶1, John A. Lawson^||, and Paul H. Axelsen²

From the Departments of Pharmacology, Biochemistry and Biophysics, and Medicine, Center for Neurodegenerative Disease Research, ^¶Proteomics Core Facility, Penn Genomics Institute, and the ^||Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Evidence of oxidative stress and the accumulation of fibrillar amyloid proteins (A) in senile plaques throughout the cerebral cortex are consistent features in the pathology of Alzheimer disease. To define a mechanistic link between these two processes, various aspects of the relationship between oxidative lipid membrane damage and amyloidogenesis were characterized by chemical and physical techniques. Earlier studies of this relationship demonstrated that oxidatively damaged synthetic lipid membranes promoted amyloidogenesis. The studies reported herein specify that 4-hydroxy-2-nonenal (HNE) is produced in both synthetic lipids and human brain lipid extracts by oxidative lipid damage and that it can account for accelerated amyloidogenesis. A promotes the copper-mediated generation of HNE from polyunsaturated lipids, and in turn, HNE covalently modifies the histidine side chains of A. HNE-modified A have an increased affinity for lipid membranes and an increased tendency to aggregate into amyloid fibrils. Thus, the prooxidant activity of A leads to its own covalent modification and to accelerated amyloidogenesis. These results illustrate how lipid membranes may be involved in templating the pathological misfolding of A, and they suggest a possible chemical mechanism linking oxidative stress with amyloid formation.

Received for publication, September 6, 2006 , and in revised form, December 20, 2006.

^* This work was supported by the NIA, National Institutes of Health, the American Health Assistance Foundation, and the Alzheimer Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.

¹ Present address: Amgen, Dept. of Pharmaceutics, 1 Amgen Center Dr., Thousand Oaks, CA 91320.

² To whom correspondence should be addressed: 105 Johnson Pavilion, Dept. of Pharmacology, University of Pennsylvania, 3610 Hamilton Walk, Philadelphia, PA 19104. Tel.: 215-898-9238; Fax: 215-573-2236; E-mail: axe{at}pharm.med.upenn.edu.

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