Isoorientin, a GSK-3β inhibitor, rescues synaptic dysfunction, spatial memory deficits and attenuates pathological progression in APP/PS1 model mice
Isoorientin, a GSK-3β inhibitor, rescues synaptic dysfunction, spatial memory deficits and attenuates pathological progression in APP/PS1 model mice
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DOI：
10.1016/j.bbr.2020.112968
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发表时间：
2020-10
影响因子：
2.7
通讯作者：
Xiaoqin Tan;Zhibin Liang;Yingui Li;Yingkun Zhi;Lang Yi;Shasha Bai;Kelly H Forest;R. Nichols;Yan Dong;Qing X. Li
中科院分区：
文献类型：
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作者：
Xiaoqin Tan;Zhibin Liang;Yingui Li;Yingkun Zhi;Lang Yi;Shasha Bai;Kelly H Forest;R. Nichols;Yan Dong;Qing X. Li
β-淀粉样蛋白(A-β)升高、tau蛋白过度磷酸化和神经炎症是阿尔茨海默病(AD)的主要特征。糖原合成酶激酶-3β(GSK-3β)是AD发病机制中的一个关键蛋白激酶。阻断葛兰素史克-3β是治疗AD的一种有吸引力的策略。异冬青是一种6-C-糖基黄酮类化合物，先前被证明是葛兰素史克-3β的高度选择性抑制剂，同时在阿尔茨海默病神经元模型中发挥神经保护作用。在本研究中，我们通过生化、电生理和行为学测试，评价了异乌菜素对淀粉样前体蛋白/早老素1转基因小鼠GSK-3β、tau磷酸化、Aβ沉积、神经炎性反应、长时程增强和空间记忆的影响。在8个月龄的APP/PS1小鼠中，长期口服异藜芦醇苷可减轻大脑中多种AD的致病特征，包括GSK-3β过度激活、tau过度磷酸化、Aβ沉积和神经炎症。对于神经炎症，异藜芦醇胺治疗减少了与Aβ阳性斑块相关的激活的小胶质细胞的数量，同时降低了APP/PS1小鼠大脑中促炎因子的水平。令人惊讶的是，异胡萝卜素逆转了与认知功能相关的突触长时程增强和空间记忆的缺陷。综上所述，这些发现表明，异橙皮苷是一种脑神经保护剂，可能是治疗阿尔茨海默病和相关神经退行性疾病的有前途的药物先导。
β-Amyloid (Aβ) elevation, tau hyperphosphorylation, and neuroinflammation are major hallmarks of Alzheimer’s disease (AD). Glycogen synthase kinase-3β (GSK-3β) is a key protein kinase implicated in the pathogenesis of AD. Blockade of GSK-3β is an attractive therapeutic strategy for AD. Isoorientin, a 6-C-glycosylflavone, was previously shown to be a highly selective inhibitor of GSK-3β, while exerting neuroprotective effects in neuronal models of AD. In the present study, we evaluated thein vivoeffects of isoorientin on GSK-3β, tau phosphorylation, Aβ deposition, neuroinflammatory response, long-term potentiation, and spatial memory in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice using biochemical, electrophysiological, and behavioral tests. Chronic oral administration of isoorientin to APP/PS1 mice at 8 months of age attenuated multiple AD pathogenic hallmarks in the brains, including GSK-3β overactivation, tau hyperphosphorylation, Aβ deposition, and neuroinflammation. For neuroinflammation, isoorientin treatment reduced the number of activated microglia associated with Aβ-positive plaques, and in parallel reduced the levels of pro-inflammatory factors in the brains of APP/PS1 mice. Strikingly, isoorientin reversed deficits in synaptic long-term potentiation and spatial memory relevant to cognitive functions. Together, the findings suggest that isoorientin is a brain neuroprotector and may be a promising drug lead for treatment of AD and related neurodegenerative disorders.