Accelerated Accumulation of Amyloid β Proteins on Oxidatively Damaged Lipid Membranes

Abstract

The fully developed lesion of Alzheimer's Disease is a dense plaque composed of fibrillar amyloid β-proteins with a characteristic and well-ordered β-sheet secondary structure. Because the incipient lesion most likely develops when these proteins are first induced to form β-sheet secondary structure, it is important to understand factors that induce amyloid β-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 β-sheet secondary structure in a 42-residue amyloid β-protein. We found that membranes containing oxidatively damaged phospholipids accumulated amyloid β-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 β-sheet conformation on oxidized membranes, and the plane of the β-sheet was oriented parallel to the plane of the membrane. These results indicate that oxidatively damaged phospholipid membranes promote β-sheet formation by amyloid β-proteins, and they suggest a possible role for lipid peroxidation in the pathogenesis of Alzheimer's Disease.