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 administer an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and apply an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy.Remarkably, we evidence 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 shows no significant effect upon the progenitor cell number and constitution. We demonstrate 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 identify 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.However, the existence of human adult neurogenesis has been a subject of intense scientific debate, until recently. Tobin et al. (2019) evidenced hippocampal neurogenesis persisting throughout life in the brains of centenarians and even of Alzheimer's disease (AD) patients [2]. Convincingly, they demonstrated that the density of NPCs, neuroblasts, and immature neurons significantly decreases in cases of mild cognitive impairment and in clinical AD as compared to healthy controls. In addition, various animal models of AD are characterized by diminished adult neurogenesis. In particular, triple-transgenic mice (3×Tg) show an age-dependent neurogenesis insufficiency that is detectable in the hippocampus starting at four months of age [3]. Of note, the decline of neurogenesis in this AD model precedes the manifestation of classical hallmarks of AD pathology, such as deposition of amyloid plaques and neurofibrillary tangles in the brain, as well as memory impairment. Remarkably, as a form of neuroplasticity, adult neurogenesis has been shown to modulate vulnerability to degenerative processes and influence the course of AD [4]. Moreover, various supporting adult neurogenesis treatment strategies have demonstrated their competence to counteract the pathological behavioral outcomes in murine AD models [5]. Nevertheless, the mechanisms that regulate NPC proliferation, ...