Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP4 receptor
Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP4 receptor
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DOI：
10.1111/j.1471-4159.2011.07567.x
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发表时间：
2012-03-01
影响因子：
4.7
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
--
作者：
Hoshino, Tatsuya;Namba, Takushi;Mizushima, Tohru
β-淀粉样肽（A β）是由β-和γ-分泌酶介导的β-淀粉样前体蛋白（APP）水解产生的，在阿尔茨海默病（AD）的发病机制中起重要作用。我们最近报道，前列腺素E2（PGE 2）通过EP 2和EP 4受体刺激A β的产生，EP 4受体的激活通过内吞作用和γ-分泌酶的激活刺激A β的产生。我们发现，当表达突变APP（APP 23）的转基因小鼠分别与缺乏EP 2或EP 4受体的小鼠杂交时，它们表现出更大或更小的明显认知缺陷。与对照组小鼠相比，缺乏EP 4受体的小鼠也显示出较低水平的A β斑块沉积和较少的神经元和突触损失。向APP 23小鼠口服特定EP 4受体拮抗剂AE 3 -208，改善了其认知能力，并降低了脑A β水平，抑制了γ-分泌酶的内吞作用和激活。总之，这些结果表明，抑制EP 4受体通过抑制A β产生和减少神经元和突触损失来改善APP 23小鼠的认知功能。因此，我们建议EP 4受体拮抗剂，如AE 3 -208，可能对预防和治疗AD有治疗益处。
Amyloid-beta peptide (A beta), which is generated by the beta- and gamma-secretase-mediated proteolysis of beta-amyloid precursor protein (APP), plays an important role in the pathogenesis of Alzheimers disease (AD). We recently reported that prostaglandin E2 (PGE2) stimulates the production of A beta through both EP2 and EP4 receptors and that activation of the EP4 receptor stimulates A beta production through endocytosis and activation of gamma-secretase. We here found that transgenic mice expressing mutant APP (APP23) mice showed a greater or lesser apparent cognitive deficit when they were crossed with mice lacking EP2 or EP4 receptors, respectively. Mice lacking the EP4 receptor also displayed lower levels of A beta plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP4 receptor antagonist, AE3-208 to APP23 mice, improved their cognitive performance, as well as decreasing brain levels of A beta and suppressing endocytosis and activation of gamma-secretase. Taken together, these results suggest that inhibition of the EP4 receptor improves the cognitive function of APP23 mice by suppressing A beta production and reducing neuronal and synaptic loss. We therefore propose that EP4 receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD.