Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer's Disease
Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer's Disease
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DOI：
10.3233/jad-151020
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Vina, Jose
中科院分区：
文献类型：
--
作者：
Bonet-Costa, Vicent;Herranz-Perez, Vicente;Vina, Jose
在阿尔茨海默病中，淀粉样蛋白- β (A β)从大脑中的清除减少，这是由载脂蛋白E （ApoE）促进的。ApoE通过激活RXR/PPAR二聚体受体的类视黄醇X受体片段而上调。染料木黄酮是一种无毒、经过充分测试、价格低廉的药物，可以激活受体PPAR γ的其他部分。用染料木黄酮治疗阿尔茨海默病小鼠模型，在海马学习、识别记忆、内隐记忆和气味辨别等各种认知参数方面取得了显著而迅速的改善。这与大脑中a β水平的降低、淀粉样斑块的数量和面积的降低（通过正电子发射断层扫描在体内证实）以及小胶质细胞反应性的降低有关。最后，用染料木素孵育原代星形胶质细胞导致PPAR γ介导的ApoE释放增加。我们的研究结果强烈建议应该进行对照临床试验来测试染料木素治疗人类阿尔茨海默病的效果。
Amyloid-beta (A beta) clearance from brain, which is decreased in Alzheimer's disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPAR gamma dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPAR gamma. Treatment of an Alzheimer's disease mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit memory, and odor discrimination. This is associated with a lowering of A beta levels in brain, in the number and the area of amyloid plaques (confirmed in vivo by positron emission tomography) as well as in microglial reactivity. Finally, incubation of primary astrocytes with genistein results in a PPAR gamma-mediated increased release of ApoE. Our results strongly suggest that controlled clinical trials should be performed to test the effect of genistein as treatment of human Alzheimer's disease.