Calcium signaling and synaptic maintenance in Alzheimers disease

这项多PI拨款申请的广泛和长期目标是了解钙的重要性 阿尔茨海默病(AD)突触脊椎功能障碍和丢失的信号转导。了解 导致阿尔茨海默病早期突触功能障碍和突触丢失的分子机制是早期阿尔茨海默病的关键 用于疾病检测以及开发有效的治疗干预措施。然而，主要的 在AD中导致突触功能障碍和丢失的步骤仍然知之甚少。有越来越多的人 然而，人们一致认为神经元钙信号的变化是AD发病的关键因素。 这些钙信号变化对突触长时程动态平衡和突触控制的影响 稳定性尚不明朗。在我们的研究中，我们将集中在两个主要的神经元钙信号通路-神经元 自发性囊泡释放驱动的钙离子内流途径和NMDAR的钙内流 (SVR)来自突触前终末。这两条途径都是长期活跃的，并保持基线 突触钙信号。我们的两个小组独立工作，确定了关键的钙信号转导 长期活跃并维持突触稳定的通路我们将研究 这些通路在突触维持中的作用并分析AD患者神经元中这些通路的失调 老鼠模型。具体地说，我们将(1)研究自发谷氨酸释放介导的作用 NMDAR信号在AD相关的海马区突触钙稳态改变中的作用自发 谷氨酸释放介导的钙信号测量将在原代神经元培养中进行 从早老素1 M146V敲入(PS1KI)和APP敲入(APPKI)小鼠模型；(2)研究 AD神经元突触钙稳态机制的变化。我们将检验一个假设，即 CaMKII和钙调神经磷酸酶(CaN)的活性平衡在AD神经元的突触棘中发生改变，导致 (3)评价突触钙稳态机制作为AD治疗的潜在靶点。 将在这一目标上进行药理学和遗传学实验。我们的研究取得的成果 提供有关AD患者突触丢失原因的基本机制信息，并提供新的潜力 阿尔茨海默病治疗靶点。

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.