Calcium signaling and synaptic maintenance in Alzheimers disease

这个多PI补助金申请的广泛，长期目标是了解钙的重要性 (Ca2+）阿尔茨海默病（AD）中突触棘功能障碍和丧失的信号传导。了解 导致AD中初始突触功能障碍和突触丧失的分子机制对于AD的早期发病至关重要。 疾病检测以及制定有效的治疗干预措施。但小学 导致AD中突触功能障碍和丧失的步骤仍然知之甚少。还有越来越 一致认为神经元Ca 2+信号传导的改变是AD发病机制的关键因素，然而， 这些Ca 2+信号改变对长时程突触稳态和突触调控的影响 稳定性尚不清楚。在我们的研究中，我们将集中在两个主要的神经元Ca 2+信号通路-神经元 囊泡自发释放驱动钙池调控的钙内流途径和NMDAR介导的钙内流 (SVR)从突触前末梢。这两种途径都是长期活跃的， 突触Ca 2+信号。独立工作，我们的两个小组已经确定了关键的Ca 2+信号转导 长期活跃并维持突触稳定性的通路我们将研究 这些通路在突触维持中的作用，并分析AD神经元中这些通路的失调 小鼠模型。具体来说，我们将（1）研究自发性谷氨酸释放介导的 海马突触Ca 2+稳态AD相关改变中的NMDAR信号传导自发 将用原代神经元培养物进行谷氨酸释放介导的Ca 2+信号传导测量 从早老素1 M146 V基因敲入（PS1 KI）和APP基因敲入（APPKI）小鼠模型;（2）研究 AD神经元中突触Ca 2+稳态机制的变化。我们将检验一个假设， 在AD神经元的突触棘中，CaMK II和钙调神经磷酸酶（CaN）活性的平衡发生了变化，导致 突触丢失;（3）评估突触Ca 2+稳态机制作为AD治疗的潜在靶点。 为此将进行药理学和遗传学实验。我们的研究结果 提供了关于AD中突触丢失原因的基本机制信息，并提供了新的潜力。 用于治疗AD的治疗靶点。

The broad, long-term objective of this multi-PI grant application is to understand the importance of calcium (Ca2+) signaling for synaptic spine dysfunction and loss in Alzheimer's disease (AD). Understanding the molecular mechanisms that lead to initial synaptic dysfunction and synapse loss in AD is essential for early disease detection as well as for the development of effective therapeutic interventions. However, primary steps that result in synaptic dysfunction and loss in AD remain poorly understood. There is an increasing consensus that alterations in neuronal Ca2+ signaling is a key contributor to the pathogenesis of AD, however, the impact of these Ca2+ signaling alterations on long term synapse homeostasis and control of synapse stability is unclear. In our studies we will focus on two major neuronal Ca2+ signaling pathways - neuronal store-operated Ca2+ entry (SOC) pathway and Ca2+ influx via NMDAR driven by spontaneous vesicle release (SVR) from the presynaptic terminals. Both of these pathways are active chronically and maintain baseline synaptic Ca2+ signals. Working independently, our two groups have identified key Ca2+ signaling pathways that are active chronically and maintain synapse stability We will investigate roles played by these pathways in synaptic maintenance and analyze dysregulation of these pathways in neurons from AD mouse models. Specifically, we will (1) investigate the role of spontaneous glutamate release-mediated NMDAR signaling in AD-related alterations in hippocampal synaptic Ca2+ homeostasis. Spontaneous glutamate release-mediated Ca2+ signaling measurements will be performed with primary neuronal cultures from presenilin 1 M146V knock-in (PS1KI) and APP knock-in (APPKI) mouse models; (2) investigate the changes in synaptic Ca2+ homeostatic mechanisms in AD neurons. We will test the hypothesis that a balance in activity of CaMKII and Calcineurin (CaN) is shifted in synaptic spines of AD neurons, leading to synaptic loss; (3) evaluate synaptic Ca2+ homeostatic mechanisms as potential target for AD treatment. Pharmacological and genetic experiments will be performed in this aim. Results obtained in our studies provide essential mechanistic information about causes of synaptic loss in AD and offer new potential therapeutic targets for treatment of AD.