[Ganglioside cluster-mediated aggregation and cytotoxicity of amyloid beta-peptide: molecular mechanism and inhibition].
The conversion of soluble, nontoxic amyloid beta-peptide (Abeta) to aggregated, toxic Abeta rich in beta-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 Abeta aggregation in membranes. Soluble Abeta with unordered structures specifically binds to raft-like membranes containing a ganglioside cluster, the formation of which is facilitated by cholesterol. The membrane-bound Abeta forms an alpha-helix-rich structure at lower densities. At higher densities, Abeta undergoes a conformational transition to a beta-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 Abeta fibrillization is not merely the acceleration of Abeta aggregation but the generation of toxic fibrils. Furthermore, nordihydroguaiaretic acid was found to effectively inhibit the ganglioside-induced amyloidogenesis by preventing the binding of Abeta to the membrane.
Matsuzaki
Katsumi
K
Kyoto University, Kyoto, Japan. katsumim@pharm.kyoto-u.ac.jp
D000371:Agglutination; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D003864:Depression, Chemical; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D009637:Masoprocol / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats
D016229:Amyloid beta-Peptides; D005732:Gangliosides; D009637:Masoprocol