Presenilins and neuronal calcium dyshomeostasis

早老素和神经元钙稳态失调

• 批准号: 8632540
• 负责人: Ilya B Bezprozvanny
• 金额: $ 45.91万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632540
• 关键词: Accounting; Agaricales; Aging; Aging-Related Process; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Amyloid; Brain; Calcium; Data; Defect; Dementia; Development; Disease; Down-Regulation; Elderly; Endoplasmic Reticulum; Family; Functional disorder; Future; Grant; Health; Homeostasis; Homologous Gene; Integral Membrane Protein; Ion Channel; Knockout Mice; Lead; Link; Location; Maintenance; Memory; Memory Loss; Missense Mutation; Modeling; Mutate; Mutation; Neurons; Pathogenesis; Pathway interactions; Pattern; Peptides; Phase; Play; Potassium Channel; Presenile Alzheimer Dementia; Process; Proteins; Publishing; Research; Role; Ryanodine Receptors; Series; Signal Transduction; Structure; Synapses; Testing; Vertebral column; Work; aging brain; familial Alzheimer disease; in vitro Model; memory retention; mouse model; neuronal patterning; normal aging; novel; postsynaptic; presenilin; public health relevance; research study; synaptic failure; therapeutic target; therapy development

ABSTRACT The broad, long-term objective of the project is to understand the importance of neuronal calcium (Ca2+) signaling in pathogenesis of Alzheimer's disease (AD). Presenilins are transmembrane proteins localized to endoplasmic reticulum (ER). Missense mutations in presenilins account for 40% of familial AD (FAD) cases. Many FAD mutations in presenilins have been also linked to abnormal endoplasmic reticulum (ER) calcium (Ca2+) signaling. The main aim of the current proposal is to understand the connection between mutations in presenilins, dysregulation of neuronal ER Ca2+ signaling and synaptic loss and dysfunction in AD. Specifically, we will focus on testing the novel hypothesis that defects in ER Ca2+ signaling may lead to destabilization of "mushroom spines" widely considered to be physical units for memory storage by attacking these aims:. 1. To investigate the importance of postsynaptic store-operated calcium (SOC) entry pathway downregulation in loss of mature synaptic spines in AD. Our preliminary data suggest that the increase in neuronal ER Ca2+ levels leads to a compensatory downregulation of neuronal store-operated Ca2+ entry pathway (nSOC). We discovered that the downregulation of nSOC occurs due to reduced expression of STIM2 protein, a master regulator of nSOC. We propose that reduction in synaptic nSOC causes destabilization and eventual elimination of mushroom spines, leading to loss of memories in FAD and aging brains. This hypothesis will be tested in experiments with PS1-FAD mouse model and STIM2 conditional knockout mouse model. 2. To investigate the connection between dysregulation of neuronal activity and destabilization of LTP- induced mature synaptic spines in AD. Our preliminary data indicate that appropriate pattern of neuronal activity is critical for maintenance of mature "mushroom spines". We further discovered that abnormal ER Ca2+ signaling causes disruption of this pattern in PS1-FAD neurons. We will perform a series of experiments aimed at dissecting the connection between ER Ca2+ homeostasis, neuronal activity pattern and stability of mushroom spines in AD neurons. We will evaluate a crucial role of intracellular Ca2+ stores and SK family of Ca2+-activated potassium channels in this process. 3. To analyze the cross-talk of amyloid and calcium pathways for AD pathogenesis. A 42 oligomers influence neuronal Ca2+ signaling and neuronal activity via variety of pathways. In this aim we will investigate if some of the Ca2+-related targets and pathways explored in SA1 and SA2 may also apply to models of amyloid synaptotoxicity. These experiments will be performed with in vitro model of A 42 synaptotoxicity and with recently generated APP-KI mouse model of AD.

抽象的 该项目的广泛长期目标是了解神经元钙的重要性（CA2+） 阿尔茨海默氏病（AD）发病机理中的信号传导。 presenilins是跨膜蛋白的局限于 内质网（ER）。 Presenilins中的错义突变占家庭AD（FAD）病例的40％。 老年蛋白的许多FAD突变也与异常内质网（ER）钙有关 （CA2+）信号传导。当前建议的主要目的是了解突变之间的联系 Presenilins，AD中神经元ER CA2+信号传导和突触损失和功能障碍的失调。具体来说， 我们将专注于测试新的假设，即ER Ca2+信号传导中的缺陷可能导致不稳定 通过攻击这些目标，“蘑菇刺”被广泛认为是用于存储器存储的物理单位：。 1。调查突触后商店经营钙（SOC）入口途径的重要性 AD成熟突触刺的损失下调。 我们的初步数据表明，神经元ER Ca2+水平的增加导致补偿性 神经元存储操作的Ca2+入口途径（NSOC）的下调。我们发现 NSOC的下调是由于NSOC的主要调节剂STIM2蛋白的表达降低而发生的。 我们建议减少突触NSOC会导致不稳定和最终消除蘑菇 刺，导致时尚和衰老的大脑失去记忆。该假设将在实验中进行检验 使用PS1-FAD小鼠模型和STIM2条件敲除小鼠模型。 2。研究神经元活性失调与LTP-不稳定之间的联系 在AD中诱导成熟的突触刺。 我们的初步数据表明，适当的神经元活动模式对于维持成熟至关重要 “蘑菇刺”。我们进一步发现异常ER Ca2+信号传导会导致这种模式的破坏 在PS1-FAD神经元中。我们将执行一系列旨在解剖ER之间的连接的实验 Ca2+稳态，AD神经元中蘑菇刺的神经元活动模式和稳定性。我们将评估 在此过程中，细胞内Ca2+存储和SK家族的至关重要作用。 3。分析AD发病机理的淀粉样蛋白和钙途径的串扰。 42个低聚物通过各种途径影响神经元CA2+信号传导和神经元活性。在这个目标中我们 将调查SA1和SA2中探索的CA2+相关目标和途径是否也可能适用于 淀粉样突触毒性的模型。这些实验将使用42的体外模型进行 突触毒性和最近生成的AD的APP-KI小鼠模型。