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

本研究的目的是阐明神经元内钙离子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，突触丧失发生在早期， 在AD发病机制中起重要作用，是AD患者认知功能障碍的最佳相关因素。尽管做了很多努力， AD中突触丢失的潜在机制仍不清楚。我们最近发现， 在APPPS 1小鼠模型中，2/3的锥体神经元表现出异常长持续时间、高幅度的Ca 2+峰电位 的AD。树突状细胞Ca ~（2+）峰电位的延长与突触活动和大小的减少有关。 小鼠模型通过采用体内成像，分子和药理学方法，我们建议 确定是否产生异常树突状Ca 2+尖峰及其对突触的有害影响， 丢失是携带APP和PS1突变的小鼠中的普遍现象。我们的初步研究表明， NMDA受体依赖性的环GMP产生和环GMP调节激酶II（cGKII）的激活 调节Ca 2+从内质网向胞质溶胶的释放。我们将确定的重要作用， 在APP和PS1中产生长时间树突状Ca 2+峰的cGKII依赖性信号通路 突变小鼠为了减轻异常的长持续时间的树突状细胞Ca 2+峰的产生及其对细胞的不利影响， 结果突触可塑性，我们将调查的影响，减少cGKII活性无论是通过遗传或 在APP和PS1突变小鼠中的药理学操作。拟议的实验将揭示 树突状细胞异常钙峰产生的机制及其对突触丢失的影响 AD.拟议的研究也将产生重要的新见解，以治疗AD的治疗， cGKII抑制剂减少钙调节异常和突触丢失。

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.