p75 Neurotrophin Receptor Shapes the Dynamics of Adult Hippocampal Neurogenesis in Alzheimer's Disease

Background In the present study, we explore the intricate relationship between the adult hippocampal neurogenesis and the p75 pan-neurotrophin receptor (p75NTR), under physiological or neurodegenerative conditions, focusing on Alzheimer's Disease (AD). The hippocampal adult neurogenesis, the process of generating new neurons in the Dentate Gyrus (DG), is crucial for cognitive function and emotional resilience. Dysregulation of this process is strongly implicated in AD, a neurodegenerative disorder characterized by cognitive decline and memory impairment. p75NTR, known for its diverse functions in neuronal survival, differentiation and synaptic plasticity, emerges as a key player in modulating adult neurogenesis. In addition, its significant role in the context of AD has recently been revealed, although the exact mechanism of action remains elusive. Methods This study aims to address the connective relation of adult hippocampal neurogenesis and AD by investigating the role of the p75NTR in mouse and human neural stem cells under physiological and AD conditions. Results We firstly evaluated the impact of p75NTR in in vivo adult hippocampal neurogenesis, by performing 5-bromo-2′-deoxyuridine (BrdU) injections for detection of proliferation and immunohistochemistry analysis for key neurogenic markers in p75NTR knock-out (ko) mice, compared to the wildtype of 2-, 4-, and 6- months old mice, revealing the necessity of p75NTR, and defining its cell non-autonomous function to control neural stem cell fate. In order to investigate the role of p75NTR in AD, we have generated a mouse model by crossing the p75NTR ko mice with the 5xFAD mouse, an amyloid beta dependent mouse model of AD. Our data clearly indicate the importance of p75NTR expression for the proliferation and differentiation processes of adult neural stem cells (NSCs). Differential gene expression analysis confirmed the aforementioned properties. Finally, we investigate the p75NTR effects in human induced Pluripotent Stem Cells (hiPSCs)-derived NSCs, depicting receptor’s signaling and its dysregulation in the presence of toxic Amyloid- β in human neuronal cells. Conclusions By unraveling the pleiotropic mechanisms underlying p75NTR activation in adult neurogenesis, our research seeks to offer insights into novel mechanism of action for this neurotrophin receptor, providing potential therapeutic targets for addressing AD-related neurogenesis deficits.