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

Abstract

Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.

The contributions of metabolomics in the discovery of new therapeutic targets in Alzheimer's disease

“…In this context, recent findings demonstrated that the treatment of 3×Tg mice with the arginase inhibitor L‐norvaline induced a cognitive improvement associated with a reduction in neuroinflammation and levels of β‐amyloidosis. In addition, this treatment was able to reverse the reduction of dendritic spine density in the hippocampus [85,86].…”

Alzheimer’s disease as a chronic maladaptive polyamine stress response

“…The spatial memory was significantly improved in the treated animals, and the improvement was associated with a reduction in neuroinflammation. Additionally, we evidenced a treatment-related decline in β-amyloidosis [ 167 ], followed by an improvement in the BBB integrity [ 168 ] and neurogenesis [ 169 ]. Of note, the hippocampal levels of Arg1 protein significantly reduced following the treatment.…”

“…Our data proved that HDAC4 levels decrease dramatically following the treatment with norvaline. Moreover, its functionally active form, demonstrated a substantial reduction in levels [ 169 ]. Of importance, HDAC inhibitors are promising AD-modifying agents [ 171 ], therefore, we speculate that HDAC is partially responsible for the phenotype we observed.…”

Acute Hypoxia Elevates Arginase 2 and Induces Polyamine Stress Response in Zebrafish via Evolutionary-conserved Mechanism

“…ROS have been shown to instigate Arg1 expression levels and activity [58]. Arg2 levels also escalate signi cantly as a reaction to hypoxia, as well as bacterial lipopolysaccharides, tumor necrosis factoralpha (TNFα), and oxidized low-density lipoproteins [59]. Remarkably, Arg2 activation in mammals is associated with its translocation from the mitochondria to the cytosol [55,60].…”