NICOTINIC AGONISTS FOR TREATING ALZHEIMER'S DISEASE

这笔赠款的目标是研究大脑α7尼古丁受体及其作为开发治疗阿尔茨海默病药物的靶点的潜力。这些受体已经被发现在各种条件下具有神经保护作用，并能够改善每一个被评估物种的记忆相关行为。最近的结果还表明，这些受体与淀粉样前体蛋白(APP)衍生的多肽之间存在功能相互作用。我们建议使用GTS-21和相关化合物来评估α7尼古丁受体的这些作用，GTS-21和相关化合物是受体的选择性激动剂。研究将集中在3个模型上：1)隔海马区海马伞切断的小鼠；2)双转基因小鼠 高表达瑞典突变体APP695和突变型早老素1(PS1)的APP/PS1小鼠；3)表达α7尼古丁受体的细胞培养。目的1确定α7烟碱受体激动剂的神经保护作用是否需要激活细胞内或电压敏感的钙通道。目的2确定GTS-21和我们开发的更有效的α7受体激动剂是否对淀粉样蛋白高表达APP/PS1双转基因小鼠隔胆碱能和非胆碱能神经元的轴突切断具有保护作用。目的评价GTS-21对APP/PS1小鼠淀粉样蛋白沉积的影响，观察到长期尼古丁治疗可减少80%的淀粉样蛋白沉积。它还评估了这种药物对慢性治疗后这些动物记忆相关缺陷的影响。

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.