Early Synergy between Aβ42 and Oxidatively Damaged Membranes in Promoting Amyloid Fibril Formation by Aβ40

Vishwanath Koppaka, Cynthia Paul, Ian V. J. Murray, Paul H. Axelsen
2003 Journal of Biological Chemistry  
Oxidative lipid membrane damage is known to promote the misfolding of A␤42 into pathological ␤ structure. In fully developed senile plaques of Alzheimer's disease, however, it is the shorter and more soluble amyloid ␤ protein, A␤40, that predominates. To investigate the role of oxidative membrane damage in the misfolding of A␤40, we have examined its interaction with supported lipid monolayer membranes using internal reflection infrared spectroscopy. Oxidatively damaged lipids modestly
more » ... s modestly increased A␤40 accumulation, with adsorption kinetics and a conformation that are distinct from that of A␤42. In stark contrast, pretreatment of oxidatively damaged monolayer membranes with A␤42 vigorously promoted A␤40 accumulation and misfolding. Pretreatment of saturated or undamaged membranes with A␤42 had no such effect. Parallel studies of lipid bilayer vesicles using a dye binding assay to detect fibril formation and electron microscopy to examine morphology demonstrated that A␤42 pretreatment of oxidatively damaged membranes promoted the formation of mature A␤40 amyloid fibrils. We conclude that oxidative membrane damage and A␤42 act synergistically at an early stage to promote fibril formation by A␤40. This synergy could be detected within minutes using internal reflection spectroscopy, whereas a dyebinding assay required several days and much higher protein concentrations to demonstrate this synergy.
doi:10.1074/jbc.m301334200 pmid:12821671 fatcat:slpmuyczjjenfgdhl5vmwawwea