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