Prostaglandin E2 Stimulates the Production of Amyloid-β Peptides through Internalization of the EP4 Receptor
Prostaglandin E2 Stimulates the Production of Amyloid-β Peptides through Internalization of the EP4 Receptor
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DOI：
10.1074/jbc.m109.003269
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发表时间：
2009-07-03
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;Namba, Takushi;Mizushima, Tohru
淀粉样蛋白- β (A β)肽是由β -和γ -分泌酶对β -淀粉样蛋白前体蛋白进行蛋白水解而产生的，在阿尔茨海默病的发病机制中起重要作用。炎症也很重要。我们最近报道了前列腺素E-2 (PGE(2))，一种强炎症诱导剂，通过EP2和EP4受体刺激a β的产生，在这里我们研究了其分子机制。EP2和EP4受体的激活与细胞cAMP水平的增加和蛋白激酶A （PKA）的激活相耦合。我们发现腺苷酸环化酶和PKA抑制剂抑制EP2，而不是EP4，受体介导的A β生成刺激。相反，内吞作用抑制剂抑制EP4，但不抑制EP2，受体介导的刺激。γ -分泌酶的激活与EP4受体的激活有关，而与EP2受体无关。观察到PGE(2)依赖性的EP4受体内化，表达缺乏内化活性的突变EP4受体的细胞没有表现出PGE(2)刺激的a β产生。EP4受体与PS-1 （γ -分泌酶的催化亚基）之间存在物理相互作用。观察到PGE(2)诱导的PS-1内化和EP4、PS-1和Rab7（后期内体和溶酶体的标记物）的共定位。PS-1和Rab7在野生型小鼠的大脑中也有共定位，而在EP4受体缺失的小鼠中没有。这些结果表明，PGE(2)刺激的A β的产生涉及EP4受体介导的PS-1的内吞作用，随后是γ分泌酶的激活，以及EP2受体依赖的腺苷酸环化酶和PKA的激活，这两者在炎症介导的阿尔茨海默病的进展中都很重要。
Amyloid-beta (A beta) peptides, generated by the proteolysis of beta-amyloid precursor protein by beta- and gamma-secretases, play an important role in the pathogenesis of Alzheimer disease. Inflammation is also important. We recently reported that prostaglandin E-2 (PGE(2)), a strong inducer of inflammation, stimulates the production of A beta through EP2 and EP4 receptors, and here we have examined the molecular mechanism. Activation of EP2 and EP4 receptors is coupled to an increase in cellular cAMP levels and activation of protein kinase A (PKA). We found that inhibitors of adenylate cyclase and PKA suppress EP2, but not EP4, receptor-mediated stimulation of the A beta production. In contrast, inhibitors of endocytosis suppressed EP4, but not EP2, receptor-mediated stimulation. Activation of gamma-secretase was observed with the activation of EP4 receptors but not EP2 receptors. PGE(2)-dependent internalization of the EP4 receptor was observed, and cells expressing a mutant EP4 receptor lacking the internalization activity did not exhibit PGE(2)-stimulated production of A beta. A physical interaction between the EP4 receptor and PS-1, a catalytic subunit of gamma-secretases, was revealed by immunoprecipitation assays. PGE(2)-induced internalization of PS-1 and co-localization of EP4, PS-1, and Rab7 (a marker of late endosomes and lysosomes) was observed. Co-localization of PS-1 and Rab7 was also observed in the brain of wild-type mice but not of EP4 receptor null mice. These results suggest that PGE(2)-stimulated production of A beta involves EP4 receptor-mediated endocytosis of PS-1 followed by activation of the gamma-secretase, as well as EP2 receptor-dependent activation of adenylate cyclase and PKA, both of which are important in the inflammation-mediated progression of Alzheimer disease.