Presenilins and neuronal calcium dyshomeostasis

早老素和神经元钙稳态失调

• 批准号: 8720077
• 负责人: Ilya B Bezprozvanny
• 金额: $ 45.45万
• 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/8720077
• 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

DESCRIPTION (provided by applicant): 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 criticl 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. Abeta42 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 Abeta42 synaptotoxicity and with recently generated APP-KI mouse model of AD.

描述（由申请人提供）：该项目的广泛，长期目标是了解神经元钙（Ca 2+）信号在阿尔茨海默病（AD）发病机制中的重要性。早老素是位于内质网（ER）的跨膜蛋白。早老素的错义突变占家族性AD（FAD）病例的40%。早老素中的许多FAD突变也与异常内质网（ER）钙（Ca 2+）信号传导有关。目前的建议的主要目的是了解早老素的突变，神经元ER Ca 2+信号失调和突触丢失和功能障碍之间的联系在AD。具体来说，我们将专注于测试新的假设，即ER Ca 2+信号传导的缺陷可能会导致被广泛认为是记忆存储的物理单位的“蘑菇刺”的不稳定，通过攻击这些目标：。1.探讨突触后钙库操纵的钙通道（SOC）下调在AD中成熟突触棘丢失中的重要性。我们的初步数据表明，神经元内质网Ca ~（2+）水平的增加导致神经元钙库操纵的Ca ~（2+）进入途径（nSOC）的代偿性下调。我们发现nSOC的下调是由于STIM 2蛋白表达减少而发生的，STIM 2蛋白是nSOC的主要调节因子。我们认为，突触nSOC的减少会导致蘑菇刺的不稳定和最终消除，导致FAD和大脑老化中的记忆丧失。将在使用PS1-FAD小鼠模型和STIM 2条件性敲除小鼠模型的实验中检验该假设。2.探讨AD中神经元活动失调与LTP诱导的成熟突触棘不稳定之间的关系。我们的初步数据表明，适当的神经元活动模式是维持成熟的“蘑菇刺”的关键。我们进一步发现异常的ER Ca 2+信号导致PS1-FAD神经元中这种模式的破坏。我们将进行一系列旨在解剖AD神经元中ER Ca 2+稳态、神经元活动模式和蘑菇刺稳定性之间的联系的实验。我们将评估细胞内钙库和钙激活钾通道SK家族在这一过程中的重要作用。3.分析淀粉样蛋白和钙通道在AD发病机制中的相互作用。Abeta 42寡聚体通过多种途径影响神经元Ca 2+信号传导和神经元活性。在这一目标中，我们将调查，如果一些钙离子相关的目标和途径探索SA 1和SA 2也可以适用于淀粉样蛋白突触毒性模型。这些实验将使用Abeta 42突触毒性的体外模型和最近生成的AD的APP-KI小鼠模型进行。