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bioRxiv · 10.1101/491480

L-Norvaline, a New Therapeutic Agent against Alzheimer s disease.

Polis, B.·Srikanth, K. D.·Gurevich, V.·Gil-Henn, H.·Samson, A. O.
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Abstract

Alzheimers disease (AD) is a slowly progressive neurodegenerative disorder with an insidious onset. The disease is characterized by cognitive impairment and a distinct pathology with neuritic plaques and neurofibrillary tangles.\n\nGrowing evidence highlights the role of arginase activity in the manifestation of AD. Upregulation of arginase was shown to contribute to endothelial dysfunction, atherosclerosis, diabetes, and neurodegeneration. Regulation of arginase activity appears to be a promising approach for interfering with the pathogenesis of AD and other metabolic disorders. Therefore, the enzyme represents a novel therapeutic target.\n\nHere, we administer an arginase inhibitor L-norvaline to a mouse model of AD. Then, we evaluate the neuroprotective effect of L-norvaline using immunohistochemistry, proteomics, and quantitative polymerase chain reaction assays. Finally, we identify the biological pathways activated by the treatment.\n\nRemarkably, we find that L-norvaline treatment reverses the cognitive decline in AD mice. We show the treatment is neuroprotective as indicated by reduced beta-amyloidosis, alleviated microgliosis, and TNF transcription levels. Moreover, elevated levels of neuroplasticity related protein PSD-95 were detected in the hippocampi of mice treated with L-norvaline. Furthermore, we disclose several biological pathways, which are involved in cell survival and neuroplasticity and are activated by the treatment.\n\nThrough these modes of action, L-norvaline has the potential to improve the symptoms of AD and even interfere 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.

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Polis, B., Srikanth, K. D., Gurevich, V., Gil-Henn, H., Samson, A. O.. 2018-12-09. L-Norvaline, a New Therapeutic Agent against Alzheimer s disease.. https://doi.org/10.1101/491480

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