Secreted β-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis
Secreted β-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis
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DOI：
10.1074/jbc.273.20.12341
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发表时间：
1998-05-15
影响因子：
4.8
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Guo, Q;Robinson, N;Mattson, MP
早老素-1（PS-1）基因的突变占阿尔茨海默病（AD）的常染色体显性、早发、遗传形式的病例的大约50%，PS-1是在神经元中表达的整合膜蛋白，并且主要定位于内质网（ER）中，PS-1突变可能通过改变β-淀粉样前体蛋白（APP）的加工和/或通过参与凋亡途径来促进神经元变性。AD中APP的替代加工可能会增加神经毒性淀粉样β肽（AP）的产生，并减少神经保护性α-分泌酶衍生形式APP（sAPP α）的产生。在表达AD连锁PS-1突变（L286 V）的分化PC 12细胞中，sAPP α激活转录因子NF-κ B并阻止A β诱导的细胞凋亡。用K β诱饵DNA处理细胞可阻断sAPP α的抗凋亡作用，证明sAPP α的细胞保护作用需要NF-κ B活化。表达突变型PS-1的细胞在暴露于A β后表现出NF-κ B活性的异常模式，其特征在于NF-κ B的早期活化增强，随后是活性的长期抑制。通过kappa B诱饵DNA阻断表达突变型PS-1的细胞中NF-kappa B活性与增强的A β诱导的[Ca 2 +]（i）增加和线粒体功能障碍相关。用sAPP α处理细胞稳定[Ca 2 +]（i）和线粒体功能，并通过涉及NF-κ B活化的机制抑制氧化应激。阻断ER钙释放防止（和刺激的ER钙释放thapsigarin诱导）在细胞表达突变PS-1的凋亡，这表明突变PS-1的促凋亡作用的ER钙释放的关键作用。最后，NF-κ B在防止由ER钙释放诱导的细胞凋亡中的作用通过显示sAPP α防止毒胡萝卜素诱导的细胞凋亡的数据来证明，该作用被κ B诱饵DNA阻断。我们得出结论，sAPP α稳定细胞内钙稳态，并通过涉及NF-κ B激活的机制保护神经细胞免受突变型PS-1的促凋亡作用。这些数据进一步表明，PS-1突变导致NF-κ B调节异常，这可能使神经元易受凋亡的影响。
Mutations in the presenilin-1 (PS-1) gene account for approximately 50% of the cases of autosomal dominant, early onset, inherited forms of Alzheimer's disease (AD), PS-1 is an integral membrane protein expressed in neurons and is localized primarily in the endoplasmic reticulum (ER), PS-1 mutations may promote neuronal degeneration by altering the processing of the beta-amyloid precursor protein (APP) and/or by engaging apoptotic pathways. Alternative processing of APP in AD may increase production of neurotoxic amyloid beta-peptide (AP) and reduce production of the neuroprotective alpha-secretase-derived form of APP (sAPP alpha). In differentiated PC12 cells expressing an AD-linked PS-1 mutation (L286V), sAPP alpha activated the transcription factor NF-kappa B and prevented apoptosis induced by A beta. Treatment of cells with K beta decoy DNA blocked the antiapoptotic action of sAPP alpha, demonstrating the requirement for NF-kappa B activation in the cytoprotective action of sAPP alpha. Cells expressing mutant PS-1 exhibited an aberrant pattern of NF-kappa B activity following exposure to A beta, which was characterized by enhanced early activation of NF-kappa B followed by a prolonged depression of activity. Blockade of NF-kappa B activity in cells expressing mutant PS-1 by kappa B decoy DNA was associated with enhanced A beta-induced increases of [Ca2+](i) and mitochondrial dysfunction. Treatment of cells with sAPP alpha stabilized [Ca2+](i) and mitochondrial function and suppressed oxidative stress by a mechanism involving activation of NF-kappa B. Blockade of ER calcium release prevented (and stimulation of ER calcium release by thapsigarin induced) apoptosis in cells expressing mutant PS-1, suggesting a pivotal role for ER calcium release in the proapoptotic action of mutant PS-1. Finally, a role for NF-kappa B in preventing apoptosis induced by ER calcium release was demonstrated by data showing that sAPP alpha prevents thapsigargin-induced apoptosis, an effect blocked by kappa B decoy DNA. We conclude that sAPP alpha stabilizes cellular calcium homeostasis and protects neural cells against the proapoptotic action of mutant PS-1 by a mechanism involving activation of NF-kappa B. The data further suggest that PS-1 mutations result in aberrant NF-kappa B regulation that may render neurons vulnerable to apoptosis.