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.

摘要 该项目的广泛，长期目标是了解神经元钙（Ca 2+）的重要性 信号转导在阿尔茨海默病（AD）发病机制中的作用早老素是一种跨膜蛋白， 内质网（ER）。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）钙有关 (Ca2+）信令。目前的建议的主要目的是了解突变之间的联系， 早老素、神经元ER Ca 2+信号转导失调以及AD中的突触丢失和功能障碍。具体地说， 我们将集中于测试新的假设，即ER Ca 2+信号转导的缺陷可能导致细胞的不稳定， “蘑菇刺”被广泛认为是物理单位的记忆存储攻击这些目的：。 1.探讨突触后钙库操纵的钙离子内流通路在脑缺血再灌注损伤中的作用 AD中成熟突触棘丢失的下调。 我们的初步数据表明，神经元ER Ca 2+水平的增加会导致代偿性变化。 下调神经元钙库操纵的Ca 2+进入途径（nSOC）。我们发现 nSOC的下调是由于nSOC的主要调节物STIM 2蛋白的表达减少而发生的。 我们认为，突触nSOC的减少导致不稳定和最终消除蘑菇 脊椎，导致FAD和大脑老化的记忆丧失。这一假设将在实验中得到检验 用PS1-FAD小鼠模型和STIM 2条件性基因敲除小鼠模型。 2.为了研究神经元活动失调与LTP不稳定之间的联系， 在AD中诱导成熟的突触棘。 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的神经元活动是至关重要的。 蘑菇刺我们进一步发现，异常的ER Ca 2+信号传导导致这种模式的破坏， 在PS1-FAD神经元中。我们将进行一系列的实验，旨在解剖ER之间的联系 AD神经元中蘑菇棘的Ca ~（2+）稳态、神经元活动模式和稳定性我们将评估 细胞内钙库和钙激活钾通道SK家族在这一过程中起着至关重要的作用。 3.分析淀粉样蛋白和钙通道在AD发病机制中的相互作用。 A42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。为此，我们 将研究SA 1和SA 2中探索的一些Ca 2+相关靶点和途径是否也适用于 淀粉样蛋白突触毒性的模型。这些实验将用A42的体外模型进行 突触毒性和最近产生的AD的APP-KI小鼠模型。