Papadopoulou, M. A. | bioRxiv Science

bioRxiv2025

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

Adult hippocampal neurogenesis is essential for cognitive flexibility and emotional resilience, and its disruption is strongly associated with Alzheimers disease, a disorder marked by cognitive decline and memory impairment. The p75 neurotrophin receptor regulates neuronal survival and plasticity, yet its contribution to adult hippocampal neurogenesis, especially under neurodegeneration, remains unclear. In this study, we investigate the role of p75NTR in Adult Neurogenesis using constitutive and conditional p75NTR knockout mice, the amyloidogenic 5xFAD model, and 5xFAD/p75NTR knockout mutants. We show that p75NTR deletion led to a significant reduction in NSC proliferation and altered neuronal differentiation in the dentate gyrus, acting in a cell non-autonomous function to control neural stem cell fate. Notably, 5xFAD/p75NTR mutants displayed exacerbated neurogenic deficits compared to 5xFAD mice. Transcriptomic profiling confirmed these alterations and supported a disease-relevant regulatory function. Parallel studies in human iPSC-derived neural stem cells exposed to amyloid-{beta} showed p75NTR-dependent mechanisms mirroring findings from the mouse models. Collectively, our findings establish p75NTR as a critical regulator of adult hippocampal neurogenesis, under Alzheimers Disease and propose it as a therapeutic target.

neuroscience↗

bioRxiv2023

Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer's Disease

Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimers Disease (AD) pathology. Addressing these impairments is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations. In our study, we use a combination of mouse and human stem cell models to circumvent these issues and perform comprehensive characterization of a novel neurogenic compound using in vitro screening. Our work focuses on the brain-derived neurotrophic factor (BDNF) pathway, a pivotal neurotrophin in the regulation of neuronal growth and differentiation via its receptor tyrosine receptor kinase B (TrkB). We describe the design, chemical synthesis and biological characterization of ENT-A011, a steroidal dehydroepiandrosterone (DHEA) derivative and BDNF mimetic with neuroprotective and neurogenic actions. The compound is able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Amyloid-{beta} (A{beta}) induced cell death, acting specifically through TrkB activation. The compound is also able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from A{beta} toxicity and prevent synapse loss after A{beta} treatment. To provide a translational link to human cells, we also used neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. Our findings suggest that ENT-A011 successfully induces proliferation and prevents cell death after A{beta} toxicity of human NPCs. Additionally, using RNAseq profiling, we demonstrate that the compound acts through a core gene network shared with BDNF. Our work characterizes a novel synthetic BDNF mimetic with potential neurogenic and neuroprotective actions in Alzheimers disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.

pharmacology and toxicology↗