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

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

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish
Pages (from-to)1562-1572
Number of pages11
JournalNeural Regeneration Research
Issue number9
StatePublished - 1 Sep 2019

Bibliographical note

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

Publisher Copyright:
© 2019 Medknow. All rights reserved.


  • arginase inhibition
  • arginine
  • cytokines
  • dementia
  • mTOR
  • microgliosis
  • neurodegeneration
  • neuroinflammation
  • tumor necrosis factor
  • urea cycle


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