Microsomal prostaglandin E synthase-1 is induced in alzheimer's disease and its deletion mitigates alzheimer's disease-like pathology in a mouse model
Microsomal prostaglandin E synthase-1 is induced in alzheimer's disease and its deletion mitigates alzheimer's disease-like pathology in a mouse model
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DOI：
10.1002/jnr.23217
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发表时间：
2013-07-01
影响因子：
4.2
通讯作者：
Takahashi, Mitsuo
中科院分区：
文献类型：
--
作者：
Akitake, Yoshiharu;Nakatani, Yoshihito;Takahashi, Mitsuo
流行病学研究表明，长期使用抑制环氧合酶（考克斯）活性的非甾体类抗炎药可缓解阿尔茨海默病（AD）的发作或进展。因此，已经表明前列腺素E2（PGE 2），考克斯的主要终产物，可能在AD中起致病作用，但是PGE合酶（PGES），考克斯下游的末端酶，的参与尚未完全阐明。在这里，我们发现，在三个PGES酶，只有微粒体PGES-1（mPGES-1）的诱导，其表达与β-淀粉样蛋白（A）斑块在人类AD患者和Tg 2576小鼠，一种转基因AD小鼠模型的大脑皮层。此外，为了研究mPGES-1是否有助于AD样病理学，我们将mPGES-1缺陷小鼠与Tg 2576小鼠交配。我们发现mPGES-1缺失减少了Tg 2576小鼠老年斑周围小胶质细胞的积累，并减轻了学习障碍。这些结果表明mPGES-1在AD脑中被诱导，因此在AD病理学中起作用。阻断mPGES-1可能成为AD患者新的治疗策略的基础。Inc. (c)2013 Wiley Periodicals，Inc.
Epidemiological studies have suggested that long-term use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX) activity can moderate the onset or progression of Alzheimer's disease (AD). Thus it has been suggested that prostaglandin E2 (PGE2), a major end-product of COX, may play a pathogenic role in AD, but the involvement of PGE synthase (PGES), a terminal enzyme downstream from COX, has not been fully elucidated. Here we found that, among three PGES enzymes, only microsomal PGES-1 (mPGES-1) is induced, and its expression is associated with -amyloid (A) plaques in the cerebral cortex in human AD patients and in Tg2576 mice, a transgenic AD mouse model. Furthermore, to investigate whether mPGES-1 contributes to AD-like pathology, we bred mPGES-1-deficient mice with Tg2576 mice. We found that mPGES-1 deletion reduced the accumulation of microglia around senile plaques and attenuated learning impairments in Tg2576 mice. These results indicated that mPGES-1 is induced in the AD brain and thus plays a role in AD pathology. Blockage of mPGES-1 could form the basis for a novel therapeutic strategy for patients with AD. Inc. (c) 2013 Wiley Periodicals, Inc.