Abstract
The conversion of soluble, nontoxic amyloid β-peptide (Aβ) to aggregated, toxic Aβ rich in β-sheet structures by seeded polymerization is considered to be the key step in the development of Alzheimer's disease. Accumulated evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. Our model membrane studies revealed the following mechanism of Aβ aggregation in membranes. Soluble Aβ with unordered structures specifically binds to raft-like membranes containing a ganglioside cluster, the formation of which is facilitated by cholesterol. The membrane-bound Aβ forms an α-helix-rich structure at lower densities. At higher densities, Aβ undergoes a conformational transition to a β-sheet-rich structure that can serve as a seed for amyloid fibril formation. This model was confirmed at a cellar level using rat pheochromocytoma PC12 cells. Amyloid fibrils formed in lipid rafts were cytotoxic, whereas fibrils formed in solution were almost nontoxic and had different morphologies. Thus, the role of membranes in Aβ fibrillization is not merely the acceleration of Aβ aggregation but the generation of toxic fibrils. Furthermore, nordihydroguaiaretic acid was found to effectively inhibit the ganglioside-induced amyloidogenesis by preventing the binding of Aβ to the membrane.
