Ap has long been considered a major suspect as a causative agent for Alzheimer's disease, but the mecha- nisms by which it may act have proven illusive, diverse and confusing. Our biophysical hypothesis thatA(3 oligomers reduce the thickness of the bilayer and enhance the solubility of water in its outer regions explains this effect. It predicts that amyloid oligomers should also alter the properties of voltage-dependent channels responsible for the activity of brains and muscles, and preliminary data confirm that this is actually the case for the voltage-dependent channel, Kv1.3. Soluble monomers and fibrils have no effect, and antibodies spe- cific to the oligomeric form prevent the induced conductance increases. Neutron reflectometry reveals struc- tural changes in the bilayer induced by Ap oligomers consistent with our hypothesis for the toxic action of amyloids. The oligomer species also seems to be the physical form actually responsible for the early pathol- ogy of Alzheimer's. Building on these preliminary data we propose to: 1. Investigate the mechanisms by which amyloid oligomers increase lipid bilayer conductance. Here we will measure conductancechanges induced by amyloids using a variety of well-studied conduc- tance probe mechanisms and use these results to refine our model of how amyloids exert their toxic effects. 2. Investigate the effects of amyloid peptides on cell membranes and biological conductance mechanisms. Here we will measure the effects of amyloids on Kv1.3, for which we already have exciting preliminary data, and on voltage-dependent calcium channels expressed in oocytes. Our results will be used to guide experiments in Research Project 2 as well as the simulations and modeling in Research Project 3. Results of these projects will in turn be used to guide our experiments.

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