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- Title
Ganglioside-mediated aggregation of amyloid β-proteins (Aβ): comparison between Aβ-(1-42) and Aβ-(1-40).
- Authors
Ogawa, Mariko; Tsukuda, Miho; Yamaguchi, Takahiro; Ikeda, Keisuke; Okada, Takuma; Yano, Yoshiaki; Hoshino, Masaru; Matsuzaki, Katsumi
- Abstract
Conversion of the soluble, non-toxic amyloid b-protein (Ab) into an aggregated, toxic form rich in b-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 Ab-(1–40) specifically bound to a ganglioside cluster forms cytotoxic fibrils via a conformational transition from an a-helixrich structure to a b-sheet-rich one. In the present study, we compared the interaction of Ab (1–40) and Ab-(1–42) with both model and living cell membranes. Ab-(1–42) exhibited lipid specificity and affinity similar to Ab-(1–40), though its amyloidogenic activity was more than 10-fold that of Ab-(1–40). Antibody staining experiments, using the A11 antibody specific to Ab 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. Ab-(1– 40) formed long fibrils extruding to the aqueous phase, whereas Ab-(1–42) fibrils appeared to be laterally co-assembled and short.
- Subjects
ALZHEIMER'S disease; AMYLOID beta-protein; CELL membranes; OLIGOMERS; CELL death; FLUORESCENCE microscopy; GANGLIOSIDES
- Publication
Journal of Neurochemistry, 2011, Vol 116, Issue 5, p851
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2010.06997.x