ELECTROPHYSIOLOGY OF AB OLIGOMER INTERACTION /CONDUCTANCE MECHANISMS IN CELLS/BLM

长期以来，AP一直被认为是阿尔茨海默病的主要嫌疑人，但其机制- 事实证明，它可能采取的行动是虚幻的、多样的和令人困惑的。我们的生物物理学假设A（3 低聚物降低了双层的厚度，并提高了其外部区域的水溶解度， 这种效果。它预测淀粉样蛋白低聚物也应该改变电压依赖性通道的特性 负责大脑和肌肉的活动，初步数据证实了这一点。 电压依赖性通道Kv1.3。可溶性单体和原纤维没有影响，抗体特异性地 特异于寡聚体形式防止诱导的电导增加。中子反射仪揭示了 Ap寡聚体诱导的双层结构变化与我们对Ap寡聚体毒性作用的假设一致。 淀粉样蛋白低聚物种类似乎也是实际上负责早期病理的物理形式。 老年痴呆症的症状 根据这些初步数据，我们建议： 1.研究淀粉样蛋白低聚物增加脂质双层电导的机制。 在这里，我们将使用各种研究充分的β-淀粉样蛋白来测量淀粉样蛋白诱导的电导变化， 并使用这些结果来完善我们的淀粉样蛋白如何发挥其毒性作用的模型。 2.研究淀粉样肽对细胞膜的影响和生物传导机制。 在这里，我们将测量淀粉样蛋白对Kv1.3的影响，我们已经有了令人兴奋的初步数据， 和卵母细胞中表达的电压依赖性钙通道。 我们的研究结果将用于指导研究项目2的实验以及模拟和建模 研究项目3。这些项目的结果将反过来用于指导我们的实验。

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.