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INVOLVEMENT OF PROSTAGLANDIN E_2 IN PRODUCTION OF AMYLOID-b PEPTIDES BOTH IN VITRO AND IN VIVO

前列腺素 E_2 参与淀粉样蛋白-b 肽的体外和体内生产

基本信息

批准号：
20790067
负责人：
HOSHINO Tatsuya
金额：
$ 2.75万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2009
项目状态：
已结题

项目摘要

Amyloid-β peptides (Aβ., generated by proteolysis of the βamyloid precursor protein (APP) by β- and γ-secretases, play an important role in the pathogenesis of Alzheimer's 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 Aβ 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 (EP_<1-4>), EP_4 receptors alone or EP_2 and EP_4 receptors together are responsible for this PGE_2-stimulated production of Aβ in HEK293 or SH-SY5Y cells, respectively. An EP_4 receptor antagonist suppressed the PGE_2-stimulated production of Aβ in HEK293 cells. This stimulation was accompanied by an increase in cellular cAMP levels and an analogue of cAMP stimulated the production of Aβ, demonstrating that an increases in the cellular level of cAMP are responsible for the PGE_2-stimulated production of Aβ. Immunoblotting experiments and direct measurement of γsecretase activity suggested that PGE_2-stimulated production of Aβ is mediated by activation of γ-secretase but not of β-secretase. Transgenic mice expressing the mutant type of APP showed lower levels of Aβ in the brain, when they were crossed with mice lacking either EP_2 or EP_4 receptors, suggesting that PGE_2-mediated activation of EP_2 and EP_4 receptors is involved in the production of Aβ in vivo and in the pathogenesis of AD.

淀粉样β肽（Aβ，由β-和γ-分泌酶水解β淀粉样前体蛋白（APP）而产生的β-淀粉样前体蛋白（APP）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，我们表明前列腺素E_2（PGE_2）是一种强炎症诱导剂，可以刺激培养的人胚肾（HEK）293或人神经母细胞瘤（SH-SY 5 Y）细胞中Aβ的产生，这两种细胞都表达突变型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_）中<1-4>，EP_4受体单独或EP_2和EP_4受体共同参与PGE_2刺激HEK 293或SH-SY 5 Y细胞产生Aβ。EP_4受体拮抗剂可抑制PGE_2刺激HEK 293细胞产生Aβ。这种刺激伴随着细胞内cAMP水平的增加，cAMP类似物刺激Aβ的产生，表明细胞内cAMP水平的增加是PGE_2刺激Aβ产生的原因。免疫印迹实验和γ-分泌酶活性的直接测定表明，PGE_2刺激Aβ的产生是通过激活γ-分泌酶而不是β-分泌酶介导的。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Aβ水平降低，提示PGE_2介导的EP_2和EP_4受体激活参与体内Aβ的产生和AD的发病。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prevention of ultraviolet B radiation-induced epidermal damage by expression of heat shock protein 70.

通过表达热休克蛋白70来预防紫外线B辐射引起的表皮损伤。

DOI：
发表时间：
2010
期刊：
J Biol Chem 285
影响因子：
0
作者：
Matsuda M;Hoshino T;Yamashita Y;Tanaka KI;Maji D;Sato K;Adachi H;Sobue G;Ihn H;Funasaka Y;Mizushima T.
通讯作者：
Mizushima T.

Prostaglandin E2 Stimulates the Production of Amyloid-β Peptides through Internalization of the EP4 Receptor