Marambaud Philippe, Zhao Haitian, Davies Peter
Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, North Shore-Long Island Jewish Institute for Medical Research, Manhasset, NY 11030, USA.
J Biol Chem. 2005 Nov 11;280(45):37377-82. doi: 10.1074/jbc.M508246200. Epub 2005 Sep 14.
Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Abeta could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit beta5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease.
多项流行病学研究表明，适量饮用葡萄酒与较低的阿尔茨海默病发病率相关。葡萄酒富含具有潜在神经保护活性的抗氧化化合物。然而，葡萄酒摄入对阿尔茨海默病大脑神经退行性过程的有益作用所涉及的确切分子机制仍有待明确界定。在此我们表明，白藜芦醇（反式 - 3,4',5 - 三羟基芪），一种主要存在于葡萄和红酒中的天然多酚，能显著降低不同细胞系分泌的和细胞内淀粉样β（Aβ）肽的水平。白藜芦醇并不抑制Aβ的产生，因为它对产生Aβ的酶β - 和γ - 分泌酶没有影响，而是通过一种涉及蛋白酶体的机制促进细胞内Aβ的降解。实际上，几种选择性蛋白酶体抑制剂以及蛋白酶体亚基β5的siRNA定向沉默可阻止白藜芦醇诱导的Aβ减少。这些发现证明了白藜芦醇具有蛋白酶体依赖性的抗淀粉样蛋白生成活性，并表明这种天然化合物在阿尔茨海默病中具有治疗潜力。
