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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (lnsP3R) Ca2+ signaling
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Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (lnsP3R) Ca2+ signaling

机译：本构cAMP反应元件结合蛋白（CREB）被早老素驱动的肌醇三磷酸受体（lnsP3R）Ca2 +信号传导激活

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摘要

Mutations in presenilins (PS) account for most early-onset familial Alzheimer's disease (FAD). Accumulating evidence suggests that disrupted Ca2+ signaling may play a proximal role in FAD specifically, and Alzheimer's disease (AD) more generally, but its links to the pathogenesis of AD are obscure. Here we demonstrate that expression of FAD mutant PS constitutively activates the transcription factor cAMP response element binding protein (CREB) and CREB target gene expression in cultured neuronal cells and AD mouse models. Constitutive CREB activation was associated with and dependent on constitutive activation of Ca2+/CaM kinase ki-nase β and CaM kinase IV (CaMKIV). Depletion of endoplasmic reticulum Ca2+ stores or plasma membrane phosphatidylinositol-bisphosphate and pharmacologic inhibition or knockdown of the expression of the inositol trisphosphate receptor (lnsP3R) Ca2+ release channel each abolished FAD PS-associated constitutive CaMKIV and CREB phosphorylation. CREB and CaMKIV phosphorylation and CREB target gene expression, including nitric oxide synthase and c-fos, were enhanced in brains of M146V-KI and 3xTg-AD mice expressing FAD mutant PS1 knocked into the mouse locus. FAD mutant PS-expressing cells demonstrated enhanced cell death and sensitivity to Ap toxicity, which were normalized by interfering with the lnsP3R-CAMKIV-CREB pathway. Thus, constitutive CREB phosphorylation by exaggerated lnsP3R Ca2+ signaling in FAD PS-expressing cells may represent a signaling pathway involved in the pathogenesis of AD.
机译：早老素（PS）突变是大多数早发家族性阿尔茨海默氏病（FAD）的原因。越来越多的证据表明，受破坏的Ca2 +信号传导可能在FAD中特别起着近端作用，而阿尔茨海默氏病（AD）更普遍，但其与AD发病机制的联系却不清楚。在这里，我们证明了在培养的神经元细胞和AD小鼠模型中，FAD突变体PS的表达可组成性激活转录因子cAMP反应元件结合蛋白（CREB）和CREB靶基因的表达。本构性CREB激活与Ca2 + / CaM激酶激酶β和CaM激酶IV（CaMKIV）的本构激活相关并取决于其。内质网Ca2 +存储或质膜磷脂酰肌醇二磷酸双磷酸的消耗以及肌醇三磷酸受体（InsP3R）Ca2 +释放通道的药理抑制或敲除均废除了FAD PS相关的组成型CaMKIV和CREB磷酸化。 CR146和CaMKIV磷酸化和CREB靶基因的表达，包括一氧化氮合酶和c-fos，在表达FAD突变PS1进入小鼠基因座的M146V-KI和3xTg-AD小鼠的大脑中得到增强。 FAD突变体表达PS的细胞表现出增强的细胞死亡和对Ap毒性的敏感性，这通过干扰lnsP3R-CAMKIV-CREB途径得以标准化。因此，在表达FAD PS的细胞中通过过度的lnsP3R Ca2 +信号传导进行的本构性CREB磷酸化可能代表了与AD发病机制有关的信号传导途径。

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    Marioly Muller; Cesar Cardenas; Lijuan Mei; King-Ho Cheung; J. Kevin Foskett;

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    Departments of Physiology erelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

    Departments of Physiology erelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

    Departments of Physiology erelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

    Departments of Physiology erelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

    Departments of Physiology erelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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