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

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.

Norvaline reduces blood pressure and induces diuresis in rats with inherited stress-induced arterial hypertension

“…L-norvaline treatment leads to a drop in the microglia density in the hippocampi of Alzheimer's disease model mice, which is followed by a shift from activated to resting microglial phenotype [35]. Additionally, L-norvaline significantly reduces the brain levels of TNFα in the same murine model [40]. Therefore, its application in the models of hypertension might have a particular benefit.…”

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

“…Additionally, the administration of VEGF in rats with focal cerebral ischemia reduces the infarct size and enhances neurogenesis [25]. 4 Likewise, we disclosed that norvaline treatment led to a significant increase in the levels of the glial cell-derived neurotrophic factor (GDNF) receptor RET (REarranged during Transfection) [15], which is a common signaling receptor for GDNF-family ligands [26]. Of note, GDNF is down-regulated in 3×Tg mice [27], and its overexpression improves cognitive function in this AD model [28].…”

“…These authors demonstrated that NOS1 repression decreases neuronal differentiation, and vice versa, NOS1 upregulation promotes it.The semi-essential amino acid, arginine, is a mutual substrate for both NOS and arginase. Brain arginine deprivation, due to arginase over-activation, has been suggested as a cause of AD [12].Consequently, arginine supplementation [13] and/or arginase inhibition have been proposed to halt AD development [14], and have been successfully tested in AD mice [15]. Previously, we showed that arginase inhibition with norvaline upsurges the hippocampal levels of NOS3 [16], and NOS1[17] in AD model mice.Additionally, our advanced proteomics assay revealed that chronic treatment of 3×Tg mice with norvaline led to the activation of several critical for adult neurogenesis biological processes [15].One of the most significant pathways detected was the neuregulin (NRG) pathway.…”

“…This factor has been shown to increase neurogenesis in the adult hippocampus [31]. Furthermore, neural cell adhesion molecule (NCAM), a second signaling receptor of GDNF [32], demonstrated a 43% level elevation following norvaline treatment [15]. Of note, NCAM regulates synaptic plasticity [33] and mediates axonal growth in hippocampal and cortical neurons [32].…”

“…Accordingly, NGF application has emerged as a promising approach in AD therapy [36]. The neuroprotective effects of NGF are mediated via tropomyosin receptor kinase A [37], which demonstrated a significant 56% increase following norvaline treatment [15].Additionally, we disclosed a significant, more than two-fold elevation, in the levels of neuroligin-1 in the hippocampi of 3×Tg mice following treatment with norvaline [16]. Neuroligin-1 knockdown has been shown to reduce the survival rate of adult-generated newborn hippocampal neurons [38].…”