Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ann Neurol. 2012 Nov;72(5):788-98. doi: 10.1002/ana.23677. Epub 2012 Aug 22.
There is significant evidence for a central role of inflammation in the development of Alzheimer disease (AD). Epidemiological studies indicate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD. Here, we investigate the function of prostaglandin E(2) (PGE(2) ) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide.
The function of PGE(2) signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of Aβ(42) peptides. Our findings were then confirmed in young adult APPSwe-PS1ΔE9 transgenic mice.
Deletion of the PGE(2) EP3 receptor in a model of Aβ(42) peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1ΔE9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were β-secretase and β C-terminal fragment levels, suggesting that generation of Aβ peptides may be increased as a result of proinflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in presynaptic proteins seen in APPSwe-PS1ΔE9 mice.
Our findings identify the PGE(2) EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE(2) -EP3 signaling in the development of AD.
有大量证据表明炎症在阿尔茨海默病（AD）的发展中起着核心作用。流行病学研究表明，慢性使用非甾体抗炎药（NSAIDs）可降低健康老年人群患 AD 的风险。由于 NSAIDs 抑制炎症环氧化酶 COX-1 和 COX-2 的酶活性，这些发现表明下游前列腺素信号通路在 AD 的临床前发展中起作用。在这里，我们研究了前列腺素 E（2）（PGE（2））通过其 EP3 受体在 Aβ肽引起的神经炎症反应中的信号功能。
通过给予 Aβ（42）肽诱导的亚急性神经炎症模型，在体内研究了 PGE（2）通过其 EP3 受体的信号功能。然后在年轻的 APPswe-PS1ΔE9 转基因小鼠中证实了我们的发现。
在 Aβ（42）肽诱导的神经炎症模型中，PGE（2）EP3 受体的缺失减少了促炎基因表达、细胞因子产生和氧化应激。在家族性 AD 的 APPswe-PS1ΔE9 模型中，EP3 受体的缺失阻断了促炎基因和蛋白表达以及脂质过氧化的诱导。此外，Aβ肽的水平显著降低，β-分泌酶和β C 末端片段的水平也降低，这表明 Aβ肽的产生可能由于促炎 EP3 信号而增加。最后，EP3 受体的缺失显著逆转了 APPswe-PS1ΔE9 小鼠中观察到的突触前蛋白下降。
我们的发现将 PGE（2）EP3 受体确定为一种新的促炎、促淀粉样变性和突触毒性信号通路，并表明 COX-PGE（2）-EP3 信号在 AD 的发展中起作用。
