p75 neurotrophin receptor shapes the dynamics of adult hippocampal neurogenesis in Alzheimer's disease.

BACKGROUND: Alzheimer’s Disease (AD) is a neurodegenerative disorder primarily characterized by memory loss and cognitive decline. The AD-driven impairment of adult hippocampal neurogenesis - the process of generating new neurons in the dentate gyrus - is strongly implicated in this cognitive failure. Adult Neurogenesis is dependent on neurotrophin signaling, with the p75 pan-neurotrophin receptor (p75NTR) specific role to remain unclear under both physiological or pathological conditions. In the present study, we explore how p75NTR influences adult neurogenesis under both physiological and neurodegenerative conditions, focusing on AD. METHODS: We used the amyloidogenic 5xFAD mouse model of AD, as well as p75NTR full and conditional knockout mice. Moreover, we have generated a 5xFAD/p75NTR knockout model to directly examine the connective role of p75NTR in adult neurogenesis and AD. We have tempo-spatially evaluated the impact of p75NTR, by performing 5-bromo-2′-deoxyuridine injections to detect neural stem cell proliferation and immunohistochemistry analysis for key neurogenic markers. Additionally, transcriptomic profiling identified p75NTR-dependent gene networks. To extend findings to humans and provide translational relevance, we investigated p75NTR effects in human induced Pluripotent Stem Cells-derived Neural Stem Cells (iPSCs-derived NSCs), depicting receptor’s signaling in the presence of toxic Amyloid-β. RESULTS: Deletion of p75NTR in mice led to reduced NSC proliferation, altered differentiation, and decreased survival of neurons in the dentate gyrus, while our results from conditional knockout lines suggest that p75NTR regulates these processes through mechanisms extending beyond NSCs. Under AD and specifically in 5xFAD mice, neurogenesis was transiently increased at early stages but subsequently declined. This compensatory response was absent in 5xFAD/p75NTR knock out mutants, which exhibited exacerbated deficits, indicating a p75NTR-dependent disease modification. Transcriptomic analyses revealed gene networks consistent with changes in proliferation, differentiation, and survival. Finally, in human iPSCs-derived NSCs, p75NTR expression was confirmed, and receptor inhibition significantly reduced amyloid-β–induced toxicity, pointing to conserved functions across species. CONCLUSIONS: Together, these findings support a significant role for p75NTR in regulating hippocampal neurogenesis under both physiological and AD-related conditions. By linking p75NTR function to both rodent and human neural stem cell responses, this study highlights that p75NTR is not only critical for maintaining neurogenesis but also represents a candidate target for future therapeutic exploration in AD. GRAPHICAL ABSTRACT: p75NTR regulates adult hippocampal neurogenesis in vivo under physiological and Alzheimer’s disease conditions. Schematic summary of p75 neurotrophin receptor (p75NTR) function in the adult dentate gyrus of the hippocampus in vivo. Under physiological conditions, p75NTR supports neural stem cell (NSC) proliferation, proper neuronal differentiation and maturation through cell non-autonomous niche mechanisms, likely mediated by p75NTR expression in mature neurons. Deletion of p75NTR reduces NSC proliferation, leads to accumulation of immature neurons, impairs terminal neuronal maturation and increases overall cell death within the hippocampal neurogenic niche, whereas NSC-specific deletion has no effect, indicating extrinsic regulation rather than intrinsic stem cell or glial defects. In the 5xFAD mouse model of Alzheimer’s disease (AD), early disease stages exhibit a compensatory increase in NSC proliferation and immature neuron production, which is lost in 5xFAD/p75NTR ko mice. By 4 months, proliferation and immature neuron production decline in 5xFAD mice, and p75NTR deletion further exacerbates these deficits, indicating its critical role during early AD, also highlighting p75NTR as a key regulator of hippocampal neurogenesis in vivo. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01989-7.