Kawahara Kohichi, Suenobu Michita, Ohtsuka Hideyuki, Kuniyasu Akihiko, Sugimoto Yukihiko, Nakagomi Madoka, Fukasawa Hiroshi, Shudo Koichi, Nakayama Hitoshi
Department of Molecular Cell Function, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Department of Pharmaceutical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Department of Pharmaceutical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
J Alzheimers Dis. 2014;42(2):587-605. doi: 10.3233/JAD-132720.
Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-β (Aβ) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)α,β agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-β protein precursor 23 (AβPP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in AβPP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble Aβ peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble Aβ peptide in 8.5-month-old AβPP23 mice requires co-activation of RARα,β and RXRs. RARα-positive microglia accumulated Aβ plaques in the AβPP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125I-labeled oligomeric Aβ1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to Aβ clearance in Am80/HX630-treated AβPP23 mice. Am80/HX630 also increased IL-4Rα expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated AβPP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric Aβ peptides by restoring impaired IL-4 signaling in AβPP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.
阿尔茨海默病（AD）是一种神经退行性过程，涉及淀粉样β（Aβ）肽沉积、神经炎症和进行性记忆丧失。在此，我们评估了口服视黄酸受体（RAR）α、β激动剂Am80（他米巴罗汀）或特异性视黄酸X受体（RXR）泛激动剂HX630或它们的组合是否能改善AD模型——8.5月龄的淀粉样β蛋白前体23（AβPP23）小鼠的缺陷。联合给予Am80（0.5毫克/千克）和HX630（5毫克/千克）17天可显著改善AβPP23小鼠的记忆缺陷（莫里斯水迷宫实验），而单独给予任何一种药物均无效果。只有联合给药能显著降低脑中不溶性Aβ肽的水平。因此，这些结果表明，在8.5月龄的AβPP23小鼠中，通过降低不溶性Aβ肽来有效改善记忆需要同时激活RARα、β和RXR。RARα阳性的小胶质细胞在AβPP23小鼠中积累Aβ斑块。用Am80/HX630共同处理的大鼠原代小胶质细胞以胰岛素降解酶（IDE）依赖的方式显示出对125I标记的寡聚Aβ1 - 42肽的降解活性增加。联合给药在体内增加了IDE的mRNA和膜相关IDE蛋白，表明IDE有助于Am80/HX630处理的AβPP23小鼠中的Aβ清除。Am80/HX630还增加了小胶质细胞MG5细胞中IL - 4Rα的表达。Am80/HX630处理的AβPP23小鼠记忆的改善与海马白细胞介素 - 4（IL - 4）的水平和信号传导相关。因此，Am80/HX630可能通过恢复AβPP23小鼠中受损的IL - 信号来促进IL - 4反应性M2样小胶质细胞的分化，并增加它们清除寡聚Aβ肽的活性。RAR和RXR激动剂联合治疗可能是一种有效的AD治疗方法。
