Ganglioside-mediated aggregation of amyloid β-proteins (Aβ): comparison between Aβ-(1-42) and Aβ-(1-40).
Conversion of the soluble, non-toxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is considered a key step in the development of Alzheimer's disease. Accumulating evidence suggests that lipid rafts in membranes play a pivotal role in this process. We have proposed that Aβ-(1-40) specifically bound to a ganglioside cluster forms cytotoxic fibrils via a conformational transition from an α-helix-rich structure to a β-sheet-rich one. In the present study, we compared the interaction of Aβ-(1-40) and Aβ-(1-42) with both model and living cell membranes. Aβ-(1-42) exhibited lipid specificity and affinity similar to Aβ-(1-40), though its amyloidogenic activity was more than 10-fold that of Aβ-(1-40). Antibody staining experiments, using the A11 antibody specific to Aβ oligomers, demonstrated that oligomers were not detected during the aggregation process, and cell death was observed only after significant accumulation of the proteins, suggesting that the fibril-induced disruption of cell membranes leads to the cytotoxicity. Furthermore, we succeeded in visualizing fibrils formed on cell membranes using total internal reflection fluorescence microscopy. Aβ-(1-40) formed long fibrils extruding to the aqueous phase, whereas Aβ-(1-42) fibrils appeared to be laterally co-assembled and short.
Ogawa
Mariko
M
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto, Japan.
Tsukuda
Miho
M
Yamaguchi
Takahiro
T
Ikeda
Keisuke
K
Okada
Takuma
T
Yano
Yoshiaki
Y
Hoshino
Masaru
M
Matsuzaki
Katsumi
K
D000682:Amyloid / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D008081:Liposomes; D021962:Membrane Microdomains / Q000378:metabolism*; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D005732:Gangliosides; D008081:Liposomes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)