Mechanisms and therapeutics of calcium dysregulation and synapse loss in Alzheimer's disease

这项建议的目的是阐明钙调节失调和突触丢失的机制。 阿尔茨海默病(AD)的小鼠模型。许多证据表明，突触丢失发生得较早 在AD的发病机制中，是AD患者认知功能障碍的最佳相关性。尽管付出了很大努力，但 阿尔茨海默病突触丢失的潜在机制尚不清楚。我们最近发现，层的树枝晶 在APPPS1小鼠模型中，2/3锥体神经元表现出异常长时间、高幅度的钙峰 公元一代的。树突状细胞钙尖峰的延长与突触活性和大小的减少有关。 老鼠模型。通过使用活体成像、分子和药理学方法，我们建议 确定异常树突状钙尖峰的产生及其对突触的有害影响 缺失是携带APP和PS1突变的小鼠的普遍现象。我们的初步研究表明 NMDA受体依赖的环GMP的产生及cGKII的激活 调节Ca~(2+)从内质网向胞浆释放。我们将确定它的重要作用 这种依赖cGKII的信号通路在APP和PS1中长时间树突状钙尖峰的产生 突变的小鼠。减轻异常长时间树突状钙尖峰的产生及其有害作用 对突触可塑性的影响，我们将研究cGKII活性降低的影响，无论是通过遗传还是 APP和PS1突变小鼠的药理作用。拟议的实验将揭示 大鼠脑内树突状细胞异常钙尖峰产生的机制及其对突触丢失的影响 广告。拟议的研究还将对AD的治疗产生重要的新见解 使用cGKII抑制剂减少钙调节失调和突触丢失。

The goal of this proposal is to elucidate the mechanisms underlying calcium dysregulation and synapse loss in mouse models of Alzheimer's disease (AD). Many lines of evidence have shown that synapse loss occurs early in AD pathogenesis and is the best correlate of cognitive impairment in AD patients. Despite much effort, the mechanisms underlying synaptic loss in AD remain unclear. We have recently found that the dendrites of layer 2/3 pyramidal neurons exhibit abnormally long duration, high amplitude Ca2+ spikes in the APPPS1 mouse model of AD. The prolonged dendritic Ca2+ spikes are associated with the reduction in synaptic activity and size in this mouse model. By employing in vivo imaging, molecular and pharmacological approaches, we propose to determine whether the generation of abnormal dendritic Ca2+ spikes and their detrimental impact on synapse loss are a general phenomenon in mice carrying APP and PS1 mutations. Our preliminary studies show that NMDA receptor-dependent production of cyclic GMP and activation of the cyclic GMP regulated kinase II (cGKII) regulate the release of Ca2+ from endoplasmic reticulum to the cytosol. We will determine the important role of this cGKII-dependent signaling pathway in the generation of long-duration dendritic Ca2+ spikes in APP and PS1 mutant mice. To alleviate the generation of abnormal long-duration dendritic Ca2+ spikes and their detrimental consequences on synaptic plasticity, we will investigate the impact of reducing cGKII activity either by genetic or pharmacological manipulations in APP and PS1 mutant mice. The proposed experiments will reveal the mechanisms underlying the generation of abnormal dendritic Ca2+ spikes and their impact on synapse loss in AD. The proposed studies will also generate important new insights into the therapeutic treatment of AD aiming at reducing calcium dysregulation and synapse loss with cGKII inhibitors.