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 Alzheimer’s 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-β showed p75NTR-dependent mechanisms mirroring findings from the mouse models. Collectively, our findings establish p75NTR as a critical regulator of adult hippocampal neurogenesis, under Alzheimer’s Disease and propose it as a therapeutic target.