Membrane-mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid beta proteins.
Evidence of oxidative stress and the accumulation of fibrillar amyloid beta proteins (Abeta) 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. Abeta promotes the copper-mediated generation of HNE from polyunsaturated lipids, and in turn, HNE covalently modifies the histidine side chains of Abeta. HNE-modified Abeta have an increased affinity for lipid membranes and an increased tendency to aggregate into amyloid fibrils. Thus, the prooxidant activity of Abeta 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 Abeta, and they suggest a possible chemical mechanism linking oxidative stress with amyloid formation.
Murray
Ian V J
IVJ
Departments of Pharmacology, Biochemistry and Biophysics, and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Liu
Liu
L
Departments of Pharmacology, Biochemistry and Biophysics, and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Komatsu
Hiroaki
H
Departments of Pharmacology, Biochemistry and Biophysics, and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Uryu
Kunihiro
K
Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Xiao
Gang
G
Proteomics Core Facility, Penn Genomics Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Lawson
John A
JA
Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Axelsen
Paul H
PH
Departments of Pharmacology, Biochemistry and Biophysics, and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address: axe@pharm.med.upenn.edu.
D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000633:toxicity*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002675:Child, Preschool; D006801:Humans; D008563:Membrane Lipids / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*
D016229:Amyloid beta-Peptides; D008563:Membrane Lipids