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

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

doi:10.4103/1673-5374.255980

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

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

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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.

Original language	English
Pages (from-to)	1562-1572
Number of pages	11
Journal	Neural Regeneration Research
Volume	14
Issue number	9
DOIs	https://doi.org/10.4103/1673-5374.255980
State	Published - 1 Sep 2019

Bibliographical note

Publisher Copyright:
© 2019 Medknow. All rights reserved.

Funding

help with immunohistochemistry and Dr. Tali Shalit for her help with bioinformatics analysis. Author contributions: Study design: BP, AOS; experiment implementation and data analysis: BP; western blotting: KDS; RT-PCR: VG; experiment advising and supervising: HGH; manuscript writing: BP; manuscript editing: AOS and HGH. All authors approved the final version of this paper. Conflicts of interest: None declared. Financial support: This research was supported by Marie Curie CIG Grant 322113, Leir Foundation Grant, Ginzburg Family Foundation Grant, and Katz Foundation Grant (all to AOS). Funders had no involvement in the study design; data collection, analysis, and interpretation; paper writing; or decision to submit the paper for publication. Institutional review board statement: The study was approved by the Bar-Ilan University Animal Care and Use Committee (approval No. 82-10-2017) on October 1, 2017. Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication. Data sharing statement: Datasets analyzed during the current study are available from the corresponding author on reasonable request. Plagiarism check: Checked twice by iThenticate. Peer review: Externally peer reviewed. Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Additional file: Additional Table 1: KinexTM antibody microarray data report. 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).

Funders	Funder number
Ginzburg Family Foundation
Leir Foundation
Jerold B. Katz Foundation
Seventh Framework Programme	322113
Marie Curie

Keywords

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

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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.",

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

Abstract

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Keywords

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