Abstract
The conversion of soluble, non-toxic amyloid β-protein (Aβ) to aggregated, toxic Aβ could be the key step in the development of Alzheimer's disease. Liposomal studies have proposed that Aβ-(1–40) preferentially recognizes a cholesterol-dependent cluster of gangliosides and a conformationally altered form of Aβ promotes the aggregation of the protein. Cell experiments using fluorescein-labeled Aβ-(1–40) supported this model. Here, the interaction of native Aβ-(1–42) with unfixed rat pheochromocytoma PC12 cells was visualized using the amyloid-specific dye Congo red. Aβ-(1–42) preferentially bound to ganglioside and cholesterol-rich domains of cell membranes and formed amyloids in a time-dependent manner. These observations corroborate the model involving ganglioside-mediated accumulation of Aβ. The NGF-induced differentiation of PC12 cells into neuron-like cells caused a marked increase in both gangliosides and cholesterol, and thereby greatly potentiated the accumulation and cytotoxicity of Aβ-(1–42). NGF-differentiated cells exposed to Aβ-(1–42) had degenerated neurites, in which ganglioside and cholesterol-rich domains were localized, preceding cell death. A reduction in the amount of cholesterol by the cholesterol synthesis inhibitor compactin almost nullified the formation of amyloids by Aβ-(1–42). Our system using NGF-differentiated PC12 cells and Congo red is useful for screening inhibitors of the formation of amyloids by and cytotoxicity of Aβ.
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