Development of Alzheimer's disease drug candidates promoting Aβ clearance activity of type 2 microglia

作为治疗阿尔茨海默病(AD)的新策略，我们的目标是诱导我们在活体中具有的抗炎活性。特别是，我们试图开发积极利用神经保护性抗炎型小胶质细胞(2型MG)的策略，并寻找实现这一目标的新药种子。4.5mo龄APP23小鼠一侧大脑半球注射IL-4和IL-13混合物后，2d出现CD36阳性MG，7d后A-β积聚减少。在精氨酸酶I阳性和YM1阳性细胞中观察到细胞因子诱导的CD36表达，这表明CD36阳性MG是M2样细胞(Kawahara等人提交)。我们发现，口服维甲酸受体激动剂AM80，它增加了T细胞系统中IL-4的产生，降低了APP23小鼠的脑Aβ42肽(川原等，Biol.药。公牛，2009)。这项研究可能会鼓励开发新的抗炎策略来治疗AD。

As a new strategy for treatment of Alzheimer's disease (AD), we aimed to induce the antiinflammatory activity we have in a living body. In particular, we tried to develop the strategy for which the neuroprotective anti-inflammatory type of microglia (type 2 MG) is utilized aggressively and searched the new medicine seeds which achieves this. When we administered an intracerebral microinjection of a mixture of IL-4 and IL-13 into one hemisphere of 4.5 mo old APP23 mice, CD36-positive MG was induced at 2 day, and A β accumulation was reduced at 7 day post injection. The cytokine-induced CD36 expression was observed in arginase I-positive and Ym1-positive cells, which indicates that CD36-positive MG are M2-like cells (Kawahara et al., submitted). We found that oral administration of retinoic acid receptor agonist Am80, which increased IL-4 production in T-cell system, decreased brain Aβ42 peptide in APP23 mice (Kawahara et al., Biol. Pharm. Bull., 2009). This study may encourage development of new anti-inflammatory strategies for treatment of AD.