Involvement of prostaglandin E2 in production of amyloid-β peptides both in vitro and in vivo
Involvement of prostaglandin E2 in production of amyloid-β peptides both in vitro and in vivo
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DOI：
10.1074/jbc.m703087200
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发表时间：
2007-11-09
影响因子：
4.8
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
--
作者：
Hoshino, Tatsuya;Nakaya, Tadashi;Mizushima, Tohru
淀粉样β肽（A β）是由β-淀粉样前体蛋白（APP）通过β-和γ-分泌酶蛋白水解而产生的，在阿尔茨海默病（AD）的发病机制中起重要作用。炎症也被认为是AD发病机制的组成部分。在这里，我们发现前列腺素E-2（PGE（2）），一种强烈的炎症诱导剂，刺激培养的人胚肾（HEK）293或人神经母细胞瘤产生A β（SH-SY 5 Y）细胞，它们都表达突变型APP。我们已经使用亚型特异性激动剂证明，在PGE（2）受体的四种主要亚型（EP 1 -4）中，EP 4受体单独或EP 2和EP 4受体一起分别负责HEK 293或SH-SY 5 Y细胞中PGE（2）刺激的A β产生。EP 4受体拮抗剂抑制HEK 293细胞中PGE 2刺激的A β产生。这种刺激伴随着细胞cAMP水平的增加，cAMP的类似物刺激A β的产生，表明细胞cAMP水平的增加是PGE 2刺激A β产生的原因。免疫印迹实验和γ-分泌酶活性的直接测量表明，PGE 2刺激的A β的产生是由γ-分泌酶而不是β-分泌酶的激活介导的。当表达突变型APP的转基因小鼠与缺乏EP 2或EP 4受体的小鼠杂交时，其脑中A β水平较低，这表明PGE 2介导的EP 2和EP 4受体活化参与体内A β的产生和AD的发病机制。
Amyloid-beta peptides (A beta), generated by proteolysis of the beta- amyloid precursor protein ( APP) by beta- and gamma-secretases, play an important role in the pathogenesis of Alzheimer disease ( AD). Inflammation is also believed to be integral to the pathogenesis of AD. Here we show that prostaglandin E-2 (PGE(2)), a strong inducer of inflammation, stimulates the production of A beta in cultured human embryonic kidney ( HEK) 293 or human neuroblastoma ( SH- SY5Y) cells, both of which express a mutant type of APP. We have demonstrated using subtype- specific agonists that, of the four main subtypes of PGE(2) receptors (EP1-4), EP4 receptors alone or EP2 and EP4 receptors together are responsible for this PGE(2)- stimulated production of A beta in HEK293 or SH-SY5Y cells, respectively. An EP4 receptor antagonist suppressed the PGE2- stimulated production of A beta in HEK293 cells. This stimulation was accompanied by an increase in cellular cAMP levels, and an analogue of cAMP stimulated the production of A beta, demonstrating that increases in the cellular level of cAMP are responsible for the PGE2- stimulated production of A beta. Immunoblotting experiments and direct measurement of gamma-secretase activity suggested that PGE2- stimulated production of A beta is mediated by activation of gamma-secretase but not of beta-secretase. Transgenic mice expressing the mutant type of APP showed lower levels of A beta in the brain, when they were crossed with mice lacking either EP2 or EP4 receptors, suggesting that PGE2- mediated activation of EP2 and EP4 receptors is involved in the production of A beta in vivo and in the pathogenesis of AD.