Deficiency in EP4 Receptor?Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease
Deficiency in EP4 Receptor?Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease
复制标题
EP4受体相关蛋白的缺乏可改善阿尔茨海默病小鼠模型的异常焦虑样行为和脑炎症
DOI：
10.1016/j.ajpath.2017.04.010
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Minami Manabu
中科院分区：
文献类型：
--
作者：
Fujikawa Risako;Higuchi Sei;Nakatsuji Masato;Yasui Mika;Ikedo Taichi;Nagata Manabu;Hayashi Kosuke;Yokode Masayuki;Minami Manabu
小胶质细胞被认为在阿尔茨海默病（AD）的进展中起着关键作用。过度激活的小胶质细胞产生促炎细胞因子，如肿瘤坏死因子-α，似乎有助于疾病进展。先前，我们报道了前列腺素e2型4受体相关蛋白（EPRAP）促进小胶质细胞的激活。我们将人类淀粉样蛋白前体蛋白转基因小鼠从菌株J20+/−杂交到EPRAP缺乏的背景下，以确定EPRAP在AD中的作用。对5月龄雄性J20+/ - EPRAP+/+和J20+/ - EPRAP - / -小鼠进行行为学测试。EPRAP缺乏逆转了J20+/−小鼠焦虑的减少，但不影响多动症。J20+/−EPRAP+/+和J20+/−EPRAP - / -小鼠的空间记忆无显著差异。与J20+/−EPRAP+/+相比，J20+/−EPRAP−/−小鼠在前额皮质和海马中表现出较少的小胶质细胞积累和Cd68和肿瘤坏死因子-α mrna的减少。两种类型的小鼠在皮层和海马中的淀粉样蛋白-β 40或42的数量没有显著差异。与J20+/−EPRAP+/+小鼠相比，J20+/−EPRAP - /−小鼠逆转了减少的焦虑样行为，并且小胶质细胞激活减少。EPRAP在AD中的作用有待进一步研究，但我们的研究结果表明，EPRAP可能与AD患者痴呆和炎症的行为和心理症状有关。
Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2type 4 receptor–associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20+/−onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20+/−EPRAP+/+and J20+/−EPRAP−/−mice. EPRAP deficiency reversed the reduced anxiety of J20+/−mice but did not affect hyperactivity. No differences in spatial memory were observed between J20+/−EPRAP+/+and J20+/−EPRAP−/−mice. In comparison with J20+/−EPRAP+/+, J20+/−EPRAP−/−mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-α mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-β 40 or 42 in the cortex and hippocampus. J20+/−EPRAP−/−mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20+/−EPRAP+/+mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD.