Amyloid beta oligomerization is induced by brain lipid rafts.
Detergent-resistant lipid rafts are required for the generation of Abeta as they concentrate not only amyloid precursor protein (APP), but also the beta- and gamma-secretase that convert APP to Abeta. Recently, Abeta has been shown to be oligomerized, which results in neuronal cytotoxicity and synaptic failure. In this study, we have demonstrated that Abeta oligomers appeared immediately after the incubation of Abeta with lipid rafts isolated from the brain tissues of rats, and were converted into few Abeta fibrils, even after longer periods of incubation. The oligomerization of Abeta was not abolished after the brain lipid rafts were treated with heat, or with protease K, implying that the lipid raft proteins were determined not to be prerequisites for Abeta oligomerization. The cholesterol present in the lipid rafts might not be essential to Abeta oligomerization because Abeta oligomerization was not prevented after the cholesterol was removed from the lipid rafts with methyl-beta-cyclodextrin (MbetaCD). The Abeta oligomerization was accelerated by the application of lipid rafts isolated from ganglioside-rich cells, C2C12 cells, whereas this was not observed with the lipid rafts isolated from ganglioside-poor cells SK-N-MC and HeLa cells. In addition, lipid raft-induced Abeta oligomerization was shown to be inhibited in CHO-K1 cells which were defective with regard to ganglioside biosynthesis. This indicates that Abeta oligomerization requires gangliosides that are enriched in the lipid rafts.
Kim
Sang-Il
SI
School of Life Sciences and Biotechnology, Korea University, Seoul, 136-701, Korea.
Yi
Jae-Sung
JS
Ko
Young-Gyu
YG
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D019286:Endopeptidase K / Q000378:metabolism; D005732:Gangliosides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D020836:Protein Structure, Quaternary; D051381:Rats; D047392:beta-Cyclodextrins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005732:Gangliosides; D008565:Membrane Proteins; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D019286:Endopeptidase K