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Exploration of the role of gangliosides and cholesterol in the mechanism of β-amyloid neurotoxicity in Alzheimer's disease
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Alzheimer's disease (AD) is the most common form of the dementia in the aging population. β-amyloid peptide (Aβ) has been indicated as the most important hallmark of AD and also is believed to be the central trigger of the pathological changes observed in the brains of AD patients. Currently, a variety of evidence indicates that Aβ-membrane interactions play an important role in the mechanism of Aβ neurotoxicity. In particular, cholesterol and gangliosides were reported to be related closely to Aβ toxicity. In this work, we explored the role of gangliosides and cholesterol in the mechanism of Aβ neurotoxicity in AD. Specifically, we investigated the feasibility that the binding between Aβ and the cell membrane, which is proposed to be the first step in the mechanism of Aβ toxicity, might be affected by membrane dipole potential, and that cholesterol may play a role in this interaction by altering membrane dipole. Using a dual-wavelength ratiometric fluorescence method, we investigated the relationship between membrane dipole potential and interaction of Aβ with living cell membranes. Binding of Aβ to the cell membrane resulted in a decrease in membrane dipole. Reductions of membrane cholesterol content also led to a decrease in membrane dipole, suggesting that increased cholesterol content might increase membrane dipole and enhance Aβ binding and subsequent toxicity. We then examined if increasing or decreasing of membrane dipole with 6-ketocholestanol or phloretin, respectively, could alter the toxic effects of Aβ. Increasing and decreasing membrane dipole resulted in increased and decreased cell viability, respectively, upon exposure to Aβ. We also explored the hypothesis that Aβ binding to cells was via a direct affinity for gangliosides. We investigated the ability of gangliosides and ganglioside components in solution to compete with gangliosides on the membrane surface for binding of Aβ. Our results indicate that gangliosides might be the Aβ binding site on cell membrane and that an antibody against gangliosides reduces Aβ toxicity by the direct blocking of binding of Aβ to gangliosides on cell surface. Finally, we investigated via modeling the ability of ganglioside competitors to attenuate Aβ toxicity. Collectively, this body of research suggests that cholesterol and gangliosides have important roles in the mechanism of toxicity in AD. Our ability to inhibit the binding of Aβ to the cell membrane may lead to novel treatment approaches for Alzheimer's disease.
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Includes bibliographical references (leaves 73-85).
Issued also on microfiche from Lange Micrographics.
Yoo, Suk Joon (2002). Exploration of the role of gangliosides and cholesterol in the mechanism of β-amyloid neurotoxicity in Alzheimer's disease. Master's thesis, Texas A&M University. Available electronically from
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