Accelerated accumulation of amyloid beta proteins on oxidatively damaged lipid membranes.
The fully developed lesion of Alzheimer's Disease is a dense plaque composed of fibrillar amyloid beta-proteins with a characteristic and well-ordered beta-sheet secondary structure. Because the incipient lesion most likely develops when these proteins are first induced to form beta-sheet secondary structure, it is important to understand factors that induce amyloid beta-proteins to adopt this conformation. In this investigation we used a novel form of infrared spectroscopy that can characterize the conformation, orientation, and rate of accumulation of the protein on various lipid membranes to determine whether oxidatively damaged phospholipid membranes induce the formation of beta-sheet secondary structure in a 42-residue amyloid beta-protein. We found that membranes containing oxidatively damaged phospholipids accumulated amyloid beta-protein significantly faster than membranes containing only unoxidized or saturated phospholipids. Accelerated accumulation was also seen when 3 mol % G(M1) ganglioside was incorporated into a saturated phosphatidylcholine membrane. The accumulated protein more completely adopted a beta-sheet conformation on oxidized membranes, and the plane of the beta-sheet was oriented parallel to the plane of the membrane. These results indicate that oxidatively damaged phospholipid membranes promote beta-sheet formation by amyloid beta-proteins, and they suggest a possible role for lipid peroxidation in the pathogenesis of Alzheimer's Disease.
Departments of Pharmacology, and Medicine, Infectious Disease Section, The Johnson Foundation for Molecular Biophysics, University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 19104-6084, USA.
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D000327:Adsorption; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D015227:Lipid Peroxidation; D008566:Membranes; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017550:Spectroscopy, Fourier Transform Infrared; D014810:Vitamin E / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D010446:Peptide Fragments; D010743:Phospholipids; C075222:amyloid beta-protein (1-42); D014810:Vitamin E; D001205:Ascorbic Acid