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（CA2+）信号在阿尔茨海默氏病（AD）的发病机理中的重要性。 presenilins是跨膜蛋白局部局限于内质网（ER）。 Presenilins中的错义突变占家庭AD（FAD）病例的40％。老年蛋白中的许多FAD突变也与异常内质网（ER）钙（Ca2+）信号传导有关。当前建议的主要目的是了解presenilins中突变，神经元ER CA2+信号传导的失调以及AD中突触损失和功能障碍。具体而言，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会导致“蘑菇刺”通过攻击这些目标而被广泛认为是用于存储器存储的物理单位：。 1。研究突触后商店经营钙（SOC）进入途径在AD中成熟突触棘损失的重要性。我们的初步数据表明，神经元ER Ca2+水平的增加导致神经元储存的CA2+进入途径（NSOC）的补偿性下调。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，突触NSOC的减少会导致不稳定并最终消除蘑菇刺，从而导致淡入时尚和衰老的大脑的记忆力丧失。该假设将在PS1-FAD小鼠模型和STIM2有条件敲除小鼠模型的实验中进行检验。 2。研究神经元活性的失调与LTP诱导的成熟突触棘的稳定之间的联系。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”的批评。我们进一步发现，异常的ER Ca2+信号传导会导致PS1-FAD神经元中这种模式的破坏。我们将执行一系列实验，旨在剖析ER Ca2+稳态，神经元活动模式和AD神经元中蘑菇棘的稳定性之间的联系。在此过程中，我们将评估细胞内Ca2+存储和SK家族的关键作用。 3。分析AD发病机理的淀粉样蛋白和钙途径的串扰。 Abeta42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。在此目标中，我们将研究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蛋白突触毒性模型。这些实验将使用ABETA42突触毒性的体外模型以及最近生成的AD AP-KI小鼠模型进行。