Prostaglandin I2 upregulates the expression of anterior pharynx-defective-1α and anterior pharynx-defective-1β in amyloid precursor protein/presenilin 1 transgenic mice.
Prostaglandin I2 upregulates the expression of anterior pharynx-defective-1α and anterior pharynx-defective-1β in amyloid precursor protein/presenilin 1 transgenic mice.
复制标题
前列腺素 I2 上调淀粉样前体蛋白/早老素 1 转基因小鼠中前咽缺陷 1α 和前咽缺陷 1β 的表达。
DOI：
10.1111/acel.12495
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发表时间：
2016-10
期刊：
影响因子：
7.8
通讯作者：
Wang ZY
中科院分区：
文献类型：
--
作者：
Wang P;Guan PP;Guo JW;Cao LL;Xu GB;Yu X;Wang Y;Wang ZY
环氧合酶‐2 （COX‐2）最近被确定参与阿尔茨海默病（AD）的发病机制。然而，一种重要的COX‐2代谢产物前列腺素（PG） I2在AD发病机制中的作用尚不清楚。我们利用人源性和小鼠源性神经细胞以及淀粉样前体蛋白/早老素1 （APP/PS1）转基因小鼠作为模型系统，阐明了咽前缺陷(APH) - 1α和咽前缺陷- 1β诱导的机制。特别是，我们发现PGI - 2的产生在AD的发展过程中增加。然后，PGI 2在神经元细胞中的积累通过磷酸化激活PKA/CREB和JNK/c‐Jun信号通路，从而导致APH‐1α/1β的表达。由于PGI - 2是COX - 2的重要代谢副产物，NS398抑制PGI - 2可降低APH - 1α/1β在神经元细胞和APP/PS1小鼠中的表达。更重要的是，APP/PS1小鼠脑脊液（CSF）中的β‐淀粉样蛋白（Aβ）低聚物对刺激APH‐1α/1β的表达至关重要，该表达被NS398孵育阻断。最后，在AD患者的大脑中证实了APH‐1α/1β的诱导作用。因此，这些发现不仅为PGI 2诱导AD进展的机制提供了新的见解，而且有助于改善对抗AD的临床治疗。
Cyclooxygenase‐2 (COX‐2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX‐2 metabolic product, prostaglandin (PG) I2, in the pathogenesis of AD remains unknown. Using human‐ and mouse‐derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx‐defective (APH)‐1α and pharynx‐defective‐1β induction. In particular, we found that PGI 2 production increased during the course of AD development. Then, PGI 2 accumulation in neuronal cells activates PKA/CREB and JNK/c‐Jun signaling pathways by phosphorylation, which results in APH‐1α/1β expression. As PGI 2 is an important metabolic by‐product of COX‐2, its suppression by NS398 treatment decreases the expression of APH‐1α/1β in neuronal cells and APP/PS1 mice. More importantly, β‐amyloid protein (Aβ) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH‐1α/1β, which was blocked by NS398 incubation. Finally, the induction of APH‐1α/1β was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI 2‐induced AD progression but also are instrumental for improving clinical therapies to combat AD.