Although it is widely accepted that the accumulation of monomeric amyloid-beta protein into insoluble deposits is the primary event driving pathogenesis of Alzheimer's disease, the underlying mechanism by which amyloid-beta aggregates result in neurotoxicity is still unclear. The central hypothesis of this research proposal is that the adsorption, incorporation, and disruption of lipid membranes by amyloid-beta is the primary mechanism by which the protein exerts neurotoxicity. To test this hypothesis, a comprehensive biophysical study will be carried out to characterize amyloid-beta-membrane interactions and to elucidate their roles in neurotoxicity. In particular, the effects of different amyloid-beta association states and the presence of cholesterol and metal ions (factors that impact amyloid-beta neurotoxicity in vitro and in vivo) on amyloid-beta-membrane interactions, amyloid-beta fibrillogenesis, and amyloid-beta-induced neurotoxicity will be investigated in detail. The link between amyloid-beta-membrane interactions and neurotoxicity will be evaluated
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| Ratajczak, Maria K; Chi, Eva Y; Frey, Shelli L et al. (2009) Ordered nanoclusters in lipid-cholesterol membranes. Phys Rev Lett 103:028103 |
| Chi, Eva Y; Ege, Canay; Winans, Amy et al. (2008) Lipid membrane templates the ordering and induces the fibrillogenesis of Alzheimer's disease amyloid-beta peptide. Proteins 72:1-24 |
| Frey, Shelli L; Chi, Eva Y; Arratia, Cristobal et al. (2008) Condensing and fluidizing effects of ganglioside GM1 on phospholipid films. Biophys J 94:3047-64 |
| Chi, Eva Y; Frey, Shelli L; Lee, Ka Yee C (2007) Ganglioside G(M1)-mediated amyloid-beta fibrillogenesis and membrane disruption. Biochemistry 46:1913-24 |
