The retinoic acid receptor agonist Am80 increases hippocampal ADAM 10 in aged SAMP8 mice
The retinoic acid receptor agonist Am80 increases hippocampal ADAM 10 in aged SAMP8 mice
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DOI：
10.1016/j.neuropharm.2013.04.009
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发表时间：
2013-09-01
影响因子：
4.7
通讯作者：
Yoshizaki, Kazuo
中科院分区：
文献类型：
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作者：
Kitaoka, Kazuyoshi;Shimizu, Noriyuki;Yoshizaki, Kazuo
视黄酸（RA，维生素A代谢物）受体（RAR）是一种转录因子。维生素A/RA给药改善了小鼠模型中阿尔茨海默病（AD）和年龄相关的记忆/学习衰减。最近，一个去整合素和金属蛋白酶结构域蛋白10（ADAM 10）被确定为RA介导的抗AD机制的关键分子。我们研究了RAR激动剂Am 80（他米巴罗汀）对加速衰老小鼠（SAMP 8）中ADAM 10表达的长期给药效果。此外，我们估计了由ADAM 10介导的淀粉样前体蛋白（APP）、淀粉样β蛋白（A β）和多毛/分裂增强子（Hes）表达的变化。还在这些小鼠中评估了空间工作记忆和海马增殖标记物（1067）的水平。13月龄SAMP 8小鼠海马中ADAM 10 mRNA和蛋白表达显著降低; Am 80给药后其表达显著改善。此外，Am 80给药后，Hes 5和1067的表达水平恢复，工作记忆的恶化受到抑制，而APP和A β水平保持不变。我们的研究结果表明，Am 80管理有效地改善痴呆症通过激活海马ADAM 10-Notch-Hes 5增殖途径。(C)2013爱思唯尔有限公司保留所有权利。
The retinoic acid (RA, a vitamin A metabolite) receptor (RAR) is a transcription factor. Vitamin A/RA administration improves the Alzheimer's disease (AD)- and age-related attenuation of memory/learning in mouse models. Recently, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as a key molecule in RA-mediated anti-AD mechanisms. We investigated the effect of chronic administration of the RAR agonist Am80 (tamibarotene) on ADAM10 expression in senescence-accelerated mice (SAMP8). Moreover, we estimated changes in the expression of the amyloid precursor protein (APP), amyloid beta (A beta), and hairy/enhancer of split (Hes), which are mediated by ADAM10. Spatial working memory and the levels of a hippocampal proliferation marker (1067) were also assessed in these mice. ADAM10 mRNA and protein expression was significantly reduced in the hippocampus of 13-month-old SAMP8 mice; their expression improved significantly after Am80 administration. Further, after Am80 administration, the expression levels of Hes5 and 1067 were restored and the deterioration of working memory was suppressed, whereas APP and A beta levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal ADAM10-Notch-Hes5 proliferative pathway. (C) 2013 Elsevier Ltd. All rights reserved.