Resveratrol Induces Brain Resilience Against Alzheimer Neurodegeneration Through Proteostasis Enhancement
Resveratrol Induces Brain Resilience Against Alzheimer Neurodegeneration Through Proteostasis Enhancement
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DOI：
10.1007/s12035-018-1157-y
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发表时间：
2019-02-01
影响因子：
5.1
通讯作者：
Sanfeliu, Coral
中科院分区：
文献类型：
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作者：
Corpas, Ruben;Grinan-Ferre, Christian;Sanfeliu, Coral
白藜芦醇是一种天然化合物，可以模拟热量限制的抗氧化和抗衰老作用，主要通过SIRT1介导，SIRT1是一种能延长寿命和保护神经的去乙酰化酶。我们的目的是分析白藜芦醇对对照非转基因（NoTg）和AD转基因（3xTg-AD）小鼠大脑状态的影响，以了解其对年龄相关神经变性和阿尔茨海默病（AD）恢复能力的潜在诱导机制。小鼠从2月龄开始饲喂添加100mg/kg白藜芦醇的日粮。白藜芦醇给药对3xTg-AD小鼠的记忆丧失和脑部病理有完全的保护作用，对健康的NoTg小鼠也有认知增强作用。白藜芦醇改善了两种小鼠品系的探索能力，减少了焦虑，表明它们很健康。白藜芦醇减少了3xTg-AD小鼠海马中A和p-tau病理的存在。在NoTg和3xTg-AD小鼠中，蛋白平衡分析显示：(1)淀粉样蛋白降解酶neprilysin水平升高，(2)淀粉样蛋白生成分泌酶BACE1水平降低，(3)蛋白酶体蛋白水平升高，蛋白酶体活性增强。白藜芦醇还增加AMPK蛋白水平，进而上调SIRT1通路，在两种小鼠中激活PGC-1和CREB，从而导致进一步的有益变化。我们的数据表明，白藜芦醇诱导认知增强和对淀粉样蛋白和tau病理的神经保护。白藜芦醇改善健康和AD小鼠的蛋白质平衡，表明它是大脑恢复和防御由异常蛋白积累引起的神经变性的机制。
Resveratrol is a natural compound that mimics the antioxidant and antiaging effects of caloric restriction, mainly mediated through SIRT1, a deacetylase that induces longevity and neuroprotection. We aimed to analyze the effects of resveratrol on the brain status of control non-transgenic (NoTg) and AD transgenic (3xTg-AD) mice to discern the mechanisms involved in a potential inducement of resilience against age-related neurodegeneration and Alzheimer's disease (AD). Mice were fed with a diet supplemented with 100mg/kg of resveratrol from 2months of age during 10months. Resveratrol administration induced complete protection against memory loss and brain pathology in 3xTg-AD mice, and also induced cognitive enhancement in healthy NoTg mice. Resveratrol improved exploration and reduced anxiety in both mouse strains, indicative of well-being. Resveratrol reduced the presence of A and p-tau pathology in the hippocampus of the 3xTg-AD mouse. Proteostasis analysis showed the following in both NoTg and 3xTg-AD mice: (i) increased levels of the amyloid-degrading enzyme neprilysin, (ii) reduction of the amyloidogenic secretase BACE1, and (iii) increase of proteasome protein levels and enhancement of proteasome activity. Resveratrol also increased AMPK protein levels, then upregulating the SIRT1 pathway, as shown by the activation of PGC-1 and CREB in both mice, resulting in further beneficial changes. Our data demonstrated that resveratrol induces cognitive enhancement and neuroprotection against amyloid and tau pathologies. Improvement of proteostasis by resveratrol, in both healthy and AD mice, suggests that it is a mechanism of brain resilience and defense against neurodegeneration caused by the accumulation of aberrant proteins.