中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (9): 1562-1572.doi: 10.4103/1673-5374.255980

• 原著:退行性病与再生 • 上一篇    下一篇

L-正缬氨酸：一种对抗阿尔茨海默病的新型药物

  

  • 出版日期:2019-09-15 发布日期:2019-09-15
  • 基金资助:

    这项研究由Marie Curie CIG基金，Leir基金，Ginzburg Family 基金和Katz 基金资助

L-Norvaline, a new therapeutic agent against Alzheimer’s disease

Baruh Polis 1, 2 , Kolluru D. Srikanth 2 , Vyacheslav Gurevich 3 , Hava Gil-Henn 2 , Abraham O. Samson 1   

  1. 1 Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
    2 Laboratory of Cell Migration and Invasion, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
    3 Laboratory of Cancer Personalized Medicine and Diagnostic Genomics, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
  • Online:2019-09-15 Published:2019-09-15
  • Contact: Baruh Polis, MD, baruhpolis@gmail.com.
  • Supported by:

    This research was supported by Marie Curie CIG Grant 322113, Leir Foundation Grant, Ginzburg Family Foundation Grant, and Katz Foundation Grant (all to AOS).

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摘要：

越来越多的证据显示精氨酸酶活性上调促进了阿尔茨海默病（AD）神经变性，因此实验假设调节精氨酸酶活性可对抗AD发病，为了验证这一假设，实验给予阿尔茨海默病样三重转基因小鼠喂饲2.5个月250 mg/L精氨酸酶抑制剂L-正缬氨酸。以免疫组织化学、蛋白质组学和定量聚合酶链反应评估L-正缬氨酸的神经保护作用，并确定该作用发挥的的生物途径。结果发现L-正缬氨酸治疗减轻了阿尔茨海默病小鼠的认知能力下降和小胶质细胞增生，减少了β-淀粉样变性水平和肿瘤坏死因子α转录水平。同时，在L-正缬氨酸干预的小鼠海马中检测到与神经可塑性相关的突触后密度蛋白95水平升高，涉及细胞存活和神经可塑性的生物途径被激活，通过这些途径L-正缬氨酸对阿尔茨海默病发挥了神经保护作用。该研究为L-正缬氨酸成为对抗阿尔茨海默病的新型药物提供了实验证据。

orcid: 0000-0002-3496-8250 (Baruh Polis)

关键词: 痴呆, 精氨酸酶抑制, 精氨酸, 尿素循环, 小神经胶质细胞, 神经炎症, 细胞因子, 肿瘤坏死因子, mTOR, 神经退行性疾病

Abstract:

Growing evidence highlights the role of arginase activity in the manifestation of Alzheimer’s disease (AD). Upregulation of arginase was shown to contribute to neurodegeneration. Regulation of arginase activity appears to be a promising approach for interfering with the pathogenesis of AD. Therefore, the enzyme represents a novel therapeutic target. In this study, we administered an arginase inhibitor, L-norvaline (250 mg/L), for 2.5 months to a triple-transgenic model (3×Tg-AD) harboring PS1M146V, APPSwe, and tauP301L transgenes. Then, the neuroprotective effects of L-norvaline were evaluated using immunohistochemistry, proteomics, and quantitative polymerase chain reaction assays. Finally, we identified the biological pathways activated by the treatment. Remarkably, L-norvaline treatment reverses the cognitive decline in AD mice. The treatment is neuroprotective as indicated by reduced beta-amyloidosis, alleviated microgliosis, and reduced tumor necrosis factor transcription levels. Moreover, elevated levels of neuroplasticity related postsynaptic density protein 95 were detected in the hippocampi of mice treated with L-norvaline. Furthermore, we disclosed several biological pathways, which were involved in cell survival and neuroplasticity and were activated by the treatment. Through these modes of action, L-norvaline has the potential to improve the symptoms of AD and even interferes with its pathogenesis. As such, L-norvaline is a promising neuroprotective molecule that might be tailored for the treatment of a range of neurodegenerative disorders. The study was approved by the Bar-Ilan University Animal Care and Use Committee (approval No. 82-10-2017) on October 1, 2017.

Key words: dementia, arginase inhibition, arginine, urea cycle, microgliosis, neuroinflammation, cytokines, tumor necrosis factor, mTOR, neurodegeneration