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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver
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Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver

机译：Withania somnifera通过增强肝脏中的低密度脂蛋白受体相关蛋白来逆转阿尔茨海默氏病的病理

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摘要

A 30-d course of oral administration of a semipurif ied extract of the root of Withania somnifera consisting predominantly of withano-lides and withanosides reversed behavioral deficits, plaque pathology, accumulation of β-amyloid peptides (Aβ) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease trans-genic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aβ and a decrease in brain Aβ monomer after 7 d, indicating increased transport of Aβ from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aβ-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aβ levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aβ. In WT mice, the extract induced liver-, but not brain, LRP and NEP and decreased plasma and brain Aβ, indicating that increase in liver LRP and sLRP occurring independent of Aβ concentration could result in clearance of Aβ. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aβ clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.
机译：口服Withania somnifera根半纯化提取物的30天疗程，主要由withano-lides和withanosides组成，可逆转行为缺陷，斑块病理，β-淀粉样肽（Aβ）积累和中脑大脑中的低聚物和老年APP / PS1阿尔茨海默氏病转基因小鼠。它在逆转APPSwInd小鼠的行为缺陷和斑块负荷方面同样有效（J20行）。时间序列涉及7天后血浆Aβ的增加和脑Aβ单体的减少，表明Aβ从脑向外围的转运增加。低密度脂蛋白受体相关蛋白（LRP）在脑微血管和Aβ降解蛋白酶中性溶酶（NEP）中的表达增强在脑Aβ水平显着下降后14-21 d发生。但是，肝脏LRP和NEP的显着升高发生在更早的7天，并伴有血浆sLRP升高，血浆sLRP是大脑Aβ的外围吸收。在野生型小鼠中，提取物诱导肝，而非脑，LRP和NEP并降低血浆和脑Aβ，表明肝脏LRP和sLRP的升高与Aβ浓度无关而独立，可导致Aβ清除。肝脏LRP的选择性下调，而不是NEP的，下调了提取物的治疗效果。通过肝脏LRP上调介导的W. Somnifera的显着治疗作用表明，靶向外周提供了Aβ清除的独特机制，并逆转了在阿尔茨海默氏病模型中看到的行为缺陷和病理。

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    Neha Sehgal; Alok Gupta; Rupanagudi Khader Valli; Shanker Datt Joshi; Jessica T. Mills; Edith Hamel; Pankaj Khanna; Subhash Chand Jain; Suman S. Thakur; Vijayalakshmi Ravindranath;

  • 作者单位

    Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, Haryana 122050, India;

    Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, Haryana 122050, India;

    Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, Haryana 122050, India;

    Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, Haryana 122050, India;

    Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4;

    Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4;

    Department of Chemistry, University of Delhi, Delhi 110007, India;

    Department of Chemistry, University of Delhi, Delhi 110007, India;

    Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India;

    Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, Haryana 122050, India,Centre for Neuroscience, Indian Institute of Science, Bangalore 560012, India;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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  • 关键词

    herbal extract; dementia; neurodegenerative disease;

    机译：草药提取物痴呆;神经退行性疾病;

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