Department of Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan.
Neuropharmacology. 2013 Sep;72:58-65. doi: 10.1016/j.neuropharm.2013.04.009. Epub 2013 Apr 23.
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 (Aβ), and hairy/enhancer of split (Hes), which are mediated by ADAM10. Spatial working memory and the levels of a hippocampal proliferation marker (Ki67) 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 Ki67 were restored and the deterioration of working memory was suppressed, whereas APP and Aβ levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal ADAM10-Notch-Hes5 proliferative pathway.
维甲酸（RA，维生素 A 的代谢物）受体（RAR）是一种转录因子。维生素 A/RA 给药可改善阿尔茨海默病（AD）和年龄相关的记忆/学习能力下降的小鼠模型。最近，一种解整合素和金属蛋白酶域蛋白 10（ADAM10）被鉴定为 RA 介导的抗 AD 机制中的关键分子。我们研究了 RAR 激动剂 Am80（他米巴罗汀）对加速老化小鼠（SAMP8）中 ADAM10 表达的慢性给药的影响。此外，我们还评估了由 ADAM10 介导的淀粉样前体蛋白（APP）、β-淀粉样蛋白（Aβ）和毛状/增强子分裂（Hes）的表达变化。在这些小鼠中还评估了空间工作记忆和海马增殖标志物（Ki67）的水平。13 月龄 SAMP8 小鼠海马中的 ADAM10 mRNA 和蛋白表达显著降低；Am80 给药后其表达显著改善。此外，Am80 给药后，Hes5 和 Ki67 的表达水平得到恢复，工作记忆的恶化得到抑制，而 APP 和 Aβ 水平保持不变。我们的研究结果表明，Am80 给药通过激活海马 ADAM10-Notch-Hes5 增殖途径有效改善痴呆。
