NICOTINIC AGONISTS FOR TREATING ALZHEIMER'S DISEASE

这项资助的目的是研究脑α - 7烟碱受体及其作为阿尔茨海默病药物开发靶点的潜力。这些受体被发现在各种情况下都具有神经保护作用，并且能够改善每一个被评估物种的记忆相关行为。最近的研究结果也表明这些受体和淀粉样前体蛋白（APP）衍生肽之间的功能相互作用。我们建议使用GTS-21和相关化合物来评估α - 7烟碱受体的这些作用，这些化合物是受体的选择性激动剂。研究将集中在3种模型上：1)对中隔海马通路进行纤维-混合型轴切开术的小鼠；双转基因

The goal of this grant is to investigate brain alpha7 nicotinic receptors and their potential as targets for developing drugs for Alzheimer's disease. These receptors have been found to be neuroprotective under a variety of conditions as well as able to improve memory related behaviors in every species evaluated. Recent results also indicate functional interactions between these receptors and amyloid precursor protein (APP) derived peptides. We propose to evaluate these actions of alpha7 nicotinic receptors using GTS-21 and related compounds, which are selective agonists for the receptors. Studies will focus on 3 models: 1) mice that have undergone fimbria-fomix axotomy of the septohippocampal pathway; 2) double transgenic APP/PS1 mice that overexpress Swedish mutant APP695 and mutant presenilin 1 (PS1); and 3) cell cultures expressing alpha7 nicotinic receptors. Aim 1 determines if activation of intracellular or voltage sensitive calcium channels is necessary for the neuroprotective action of alpha7 nicotinic receptor agonists. Aim 2 determines whether GTS-21 and a more efficacious alpha7 receptor agonist we developed protect both septal cholinergic and non-cholinergic neurons from axotomy in amyloid-overexpressing APP/PS1 double transgenic mice. Aim 3 evaluates the effects of GTS-21 on amyloid deposition in the APP/PS1 mouse, based on the observation that chronic nicotine treatment reduces these deposits by 80%. It also evaluates the effects of this drug on memory related deficits in these animals following chronic treatment.