The urea cycle is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). Arginase-I (ARGI) accumulation at sites of amyloid-beta (Aβ) deposition is associated with L-arginine deprivation and neurodegeneration. An interaction between the arginase II (ARGII) and mTOR-ribosomal protein S6 kinase β-1 (S6K1) pathways promotes inflammation and oxidative stress. In this study, we treated triple-transgenic (3×Tg) mice exhibiting increased S6K1 activity and wild-type (WT) mice with L-norvaline, which inhibits both arginase and S6K1. The acquisition of spatial memory was significantly improved in the treated 3×Tg mice, and the improvement was associated with a substantial reduction in microgliosis. In these mice, increases in the density of dendritic spines and expression levels of neuroplasticity-related proteins were followed by a decline in the levels of Aβ toxic oligomeric and fibrillar species in the hippocampus. The findings point to an association of local Aβ-driven and immune-mediated responses with altered L-arginine metabolism, and they suggest that arginase and S6K1 inhibition by L-norvaline may delay the progression of AD.Electronic supplementary materialThe online version of this article (10.1007/s13311-018-0669-5) contains supplementary material, which is available to authorized users.

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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.