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

阿尔茨海默病钙失调和突触损失的机制和治疗

• 批准号: 9808603
• 负责人: WENBIAO GAN
• 金额: $ 25.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-04-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808603
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Calcium; Calcium Spikes; Cyclic GMP; Cytosol; Dementia; Dendrites; Elderly; Endoplasmic Reticulum; Exhibits; Functional disorder; Generations; Genetic; Goals; Health; Homosynaptic Depression; ITPR1 gene; Image; Impaired cognition; Lead; Learning; Memory; Memory Loss; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; Neurons; Pathogenesis; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Phosphotransferases; Production; Role; Signal Pathway; Signal Transduction; Synapses; Synaptic plasticity; Testing; Therapeutic; Time; cGMP production; calcium indicator; calcium metabolism; experimental study; familial Alzheimer disease; hippocampal pyramidal neuron; in vivo; in vivo imaging; inhibitor/antagonist; insight; mouse model; mutant; receptor; two photon microscopy

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.

该提案的目的是阐明钙失调和突触损失的机制 阿尔茨海默氏病的小鼠模型（AD）。许多证据表明，突触损失发生早期发生 在AD发病机理中，是AD患者认知障碍的最佳相关性。尽管付出了很多努力， AD中突触损失的机制尚不清楚。我们最近发现层的树突 2/3锥体神经元在AppPS1小鼠模型中表现出异常长的持续时间，高振幅Ca2+尖峰 广告。长时间的树突Ca2+尖峰与突触活动和大小的减小有关 鼠标模型。通过使用体内成像，分子和药理方法，我们建议 确定是否产生异常的树突状CA2+尖峰及其对突触的有害影响 损失是携带应用程序和PS1突变的小鼠中的一般现象。我们的初步研究表明 NMDA受体依赖性GMP的产生以及环状GMP调节激酶II（CGKII）的激活 调节Ca2+从内质网释放到细胞质。我们将确定 这种依赖CGKII的信号传导途径在App和PS1中产生的长期树突状Ca2+尖峰的产生 突变小鼠。减轻异常长期的树突状Ca2+尖峰的产生及其有害 对突触可塑性的后果，我们将研究通过遗传或通过遗传降低CGKII活性的影响 APP和PS1突变小鼠中的药理操作。提出的实验将揭示 产生异常树突状Ca2+尖峰的机制及其对突触损失的影响 广告。拟议的研究还将为AD瞄准的AD治疗治疗产生重要的新见解 减少CGKII抑制剂的钙失调和突触丧失时。