Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease
Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease
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DOI：
10.1096/fj.12-212118
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发表时间：
2013-02-01
期刊：
影响因子：
4.8
通讯作者：
Pasinetti, Giulio Maria
中科院分区：
文献类型：
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作者：
Ho, Lap;Ferruzzi, Mario G.;Pasinetti, Giulio Maria
流行病学和临床前研究表明，适量饮用红酒摄入的多酚可能会降低患阿尔茨海默病 (AD) 痴呆的相对风险。关于葡萄酒多酚成分可能调节 AD 的具体生物活性以及细胞和分子机制的信息有限。我们评估了口服赤霞珠红酒后大鼠大脑中多酚的积累，并测试了针对大脑的多酚是否具有潜在的有益的 AD 疾病缓解活性。我们确定了特定多酚代谢物在大脑中的积累。我们证明，与载体对照治疗相比，一种脑靶向多酚代谢物槲皮素-3-O-葡萄糖醛酸苷显着减少了 Tg2576 AD 小鼠模型中原代神经元培养物中 β-淀粉样蛋白 (Aβ) 的产生。另一种脑靶向代谢物 Malvidin-3-O-glucoside 对 Aβ 生成没有可检测到的影响。此外，在使用光诱导未修饰蛋白质交联 (PICUP) 技术的体外分析中，我们发现 quercetin-3-O-glucuronide 也能够干扰 A beta(1-40) 和 A beta(1-42) 的初始蛋白质-蛋白质相互作用，这对于形成神经毒性寡聚 A beta 物种是必需的。最后，我们发现，与载体对照治疗相比，槲皮素-3-O-葡萄糖醛酸治疗显着改善了海马形成基础突触传递和长期增强的 AD 型缺陷，这可能是通过涉及 c-Jun N 末端激酶和丝裂原激活蛋白激酶信号通路激活的机制。脑靶向槲皮素-3-O-葡萄糖醛酸可以同时调节多种独立的 AD 疾病缓解机制，因此，可能有助于膳食补充剂红酒作为 AD 的有效干预措施的益处。-Ho, L., Ferruzzi, M. G., Janle, E. M., Wang, J., Kong, B., Chen, T.-Y., Lobo, J., Cooper, B., Wu，Q.L.，Talcott，S.T.，Percival，S.S.，Simon，J.E.，Pasinetti，G.M.鉴定脑靶向生物活性膳食槲皮素-3-O-葡萄糖醛酸作为阿尔茨海默病的新型干预措施。 FASEB J. 27, 769-781 (2013)。 www.fasebj.org
Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of beta-amyloid (A beta\) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on A beta generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of A beta(1-40) and A beta(1-42) that is necessary for the formation of neurotoxic oligomeric A beta species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.-Ho, L., Ferruzzi, M. G., Janle, E. M., Wang, J., Gong, B., Chen, T.-Y., Lobo, J., Cooper, B., Wu, Q. L., Talcott, S. T., Percival, S. S., Simon, J. E., Pasinetti, G. M. Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease. FASEB J. 27, 769-781 (2013). www.fasebj.org