Membrane mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid beta  proteins

doi:10.1074/jbc.M608589200

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Papers In Press, published online ahead of print January 24, 2007
J. Biol. Chem, 10.1074/jbc.M608589200
Submitted on September 6, 2006
Accepted on January 24, 2007

Membrane mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid $beta$ proteins

Ian V.J. Murray, Liu Liu, Hiroaki Komatsu, Kunihiro Uryu, Gang Xiao, John A. Lawson, and Paul H. Axelsen

Pharmacology, Univ of Pennsylvania, Philadelphia, PA 19104-6084

Corresponding Author: axe{at}pharm.med.upenn.edu

Evidence of oxidative stress, and the accumulation of fibrillar amyloid b proteins (Ab) in senile plaques throughout the cerebral cortex, are consistent features in the pathology of Alzheimer’s 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. Ab promotes the copper-mediated generation of HNE from polyunsaturated lipids and HNE, in turn, covalently modifies the histidine side chains of Ab. HNE-modified Ab have an increased affinity for lipid membranes, and an increased tendency to aggregate into amyloid fibrils. Thus, the prooxidant activity of Ab 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 Ab, and they suggest a possible chemical mechanism linking oxidative stress with amyloid formation.

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Membrane mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid proteins

Membrane mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid $beta$ proteins