通过染料木黄酮激活PPARγ/ApoE清除β-淀粉样蛋白是治疗实验性阿尔茨海默病的一种方法。

Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer's Disease.

作者信息

Bonet-Costa Vicent, Herranz-Pérez Vicente, Blanco-Gandía MariCarmen, Mas-Bargues Cristina, Inglés Marta, Garcia-Tarraga Patricia, Rodriguez-Arias Marta, Miñarro Jose, Borras Consuelo, Garcia-Verdugo Jose Manuel, Viña Jose

机构信息

Department of Physiology, Faculty of Medicine, University of Valencia/INCLIVA, Valencia, Spain.

Laboratory of Comparative Neurobiology, Institute Cavanilles, University of Valencia, CIBERNED, Valencia, Spain.

出版信息

J Alzheimers Dis. 2016;51(3):701-11. doi: 10.3233/JAD-151020.

DOI:10.3233/JAD-151020

PMID:26890773

Abstract

Amyloid-β (Aβ) 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/PPARγ dimeric receptor. Genistein, a non-toxic, well-tested, and inexpensive drug activates the other moiety of the receptor PPARγ. 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 Aβ 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 PPARγ-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.

摘要

载脂蛋白E（ApoE）可促进β淀粉样蛋白（Aβ）从大脑中的清除，而在阿尔茨海默病中这种清除作用会减弱。视黄酸X受体（RXR）/过氧化物酶体增殖物激活受体γ（PPARγ）二聚体受体的RXR部分被激活后，ApoE会上调。染料木黄酮是一种无毒、经过充分测试且价格低廉的药物，它可激活受体PPARγ的另一部分。用染料木黄酮治疗阿尔茨海默病小鼠模型，可使认知的各种参数得到显著且快速的改善，如海马体学习、识别记忆、内隐记忆和气味辨别。这与大脑中Aβ水平的降低、淀粉样斑块数量和面积的减少（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，用染料木黄酮孵育原代星形胶质细胞会导致PPARγ介导的ApoE释放增加。我们的结果强烈表明，应该进行对照临床试验，以测试染料木黄酮作为治疗人类阿尔茨海默病的效果。