GM1 ganglioside-mediated accumulation of amyloid beta-protein on cell membranes.
The conversion of soluble, nontoxic amyloid beta-protein (Abeta) to aggregated, toxic Abeta is the key step in the development of Alzheimer's disease. Liposomal studies proposed that Abeta specifically recognizes a cholesterol-dependent cluster of monosialoganglioside GM1 and a conformationally altered form of Abeta promotes the aggregation of the protein. In this study, the accumulation of Abeta on living cells was investigated for the first time. The interaction of fluorescein-labeled Abeta (FL-Abeta) with rat pheochromocytoma PC12 cells was visualized using confocal laser microscopy. FL-Abeta was found to colocalize with GM1-rich domains on cell membranes and to accumulate in a concentration- and time-dependent manner, leading to cytotoxicity. Cholesterol depletion significantly reduced Abeta accumulation. These observations corroborate the GM1-mediated Abeta accumulation model.
Wakabayashi
Masaki
M
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Okada
Takuma
T
Kozutsumi
Yasunori
Y
Matsuzaki
Katsumi
K
D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D005677:G(M1) Ganglioside / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D008657:Metabolic Clearance Rate; D016716:PC12 Cells; D051381:Rats
D016229:Amyloid beta-Peptides; D005677:G(M1) Ganglioside; D002784:Cholesterol