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.
Highlights
The adult murine brain continuously generates neuronal progenitor cells (NPCs) in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus [1]
Since norvaline elevates NOS3 levels [16], we suggest a significant involvement of vascular endothelial growth factor (VEGF) activation in the phenotype observed following norvaline treatment
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]
Summary
The adult murine brain continuously generates neuronal progenitor cells (NPCs) in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus [1]. Reif et al (2004) reported a significant decrease in NPC proliferation in the SGZ of NOS3 knockout mice, accompanied by a decline in the levels of vascular endothelial growth factor (VEGF) [9]. These authors suggest a principal role of NOS3 in the stimulation of neurogenesis. GDNF supports neuronal survival [29], and RET is essential for mediating the neuroprotective and neuroregenerative effects of GDNF [30] This factor has been shown to increase neurogenesis in the adult hippocampus [31]. We explore the molecular mechanisms underlying the effects of norvaline on adult neurogenesis and provide insights into their machinery
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