Neuronal Overexpression of Glycogen Synthase Kinase-3β Accelerates Age-Related Glial, Vascular, and Inflammatory Remodeling of the Murine Dentate Gyrus.
- 1Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Spanish Research Council (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain.
- 2Department of Molecular Biology, Faculty of Sciences, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
- 3Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
Abstract
Adult hippocampal neurogenesis (AHN)-the lifelong generation of new neurons in the dentate gyrus (DG)-depends on the integrity of the subgranular zone (SGZ) neurogenic niche, which comprises astrocytes, microglia, oligodendroglial cells, and a dense vascular network. Although AHN declines during aging and is impaired in Alzheimer's disease (AD), the cell-type-specific alterations within the DG underlying this decline remain poorly characterized. Given the critical role of glycogen synthase kinase-3β (GSK-3β) in AD pathogenesis and AHN regulation, we studied how the overexpression of this kinase in dentate granule cells (DGCs) remodels the cellular and vascular composition of the DG throughout life. Using a layer-resolved approach (SGZ vs. granule cell layer (GCL)) and mice of distinct ages (4-30 months), we quantified glial densities, cellular contacts, vascular architecture, and cytokine profiles in wild-type (WT) and GSK-3β-overexpressing (GSK-3β-OE) mice. In the former, aging was associated with a layer-specific reorganization, characterized by progressive astrocyte loss in the SGZ, midlife increases in GCL microglia, a reduction in oligodendroglial progenitors, and enhanced SGZ vascularization. GSK-3β overexpression accelerated age-related changes, triggering premature SGZ astrocyte depletion by 4 months, broader disruption featuring reduced SGZ microglial and mature oligodendrocyte densities accompanied by increased microglial morphological complexity, vascular restructuring, and a shift toward a pro-inflammatory environment. Therefore, neuronal GSK-3β overexpression promoted a non-cell-autonomous reorganization of the DG, consistent with premature remodeling of the neurogenic niche. These results provide mechanistic insights into AHN failure in AD and point to the modulation of GSK-3β activity as a strategy to preserve DG integrity.
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BibTeX
@article{pradanossenen2026neuronal,
title = {{Neuronal Overexpression of Glycogen Synthase Kinase-3β Accelerates Age-Related Glial, Vascular, and Inflammatory Remodeling of the Murine Dentate Gyrus.}},
author = {Ana V Prádanos-Senén and Carla B Rodríguez-Moreno and María Llorens-Martín},
journal = {Glia},
year = {2026},
month = oct,
doi = {10.1002/glia.70248},
url = {https://europepmc.org/article/MED/42897854},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Neuronal Overexpression of Glycogen Synthase Kinase-3β Accelerates Age-Related Glial, Vascular, and Inflammatory Remodeling of the Murine Dentate Gyrus.
AU - Ana V Prádanos-Senén
AU - Carla B Rodríguez-Moreno
AU - María Llorens-Martín
PY - 2026
DA - 2026/10/30
JO - Glia
DO - 10.1002/glia.70248
UR - https://europepmc.org/article/MED/42897854
AB - Adult hippocampal neurogenesis (AHN)-the lifelong generation of new neurons in the dentate gyrus (DG)-depends on the integrity of the subgranular zone (SGZ) neurogenic niche, which comprises astrocytes, microglia, oligodendroglial cells, and a dense vascular network. Although AHN declines during aging and is impaired in Alzheimer's disease (AD), the cell-type-specific alterations within the DG underlying this decline remain poorly characterized. Given the critical role of glycogen synthase kinase-3β (GSK-3β) in AD pathogenesis and AHN regulation, we studied how the overexpression of this kinase in dentate granule cells (DGCs) remodels the cellular and vascular composition of the DG throughout life. Using a layer-resolved approach (SGZ vs. granule cell layer (GCL)) and mice of distinct ages (4-30 months), we quantified glial densities, cellular contacts, vascular architecture, and cytokine profiles in wild-type (WT) and GSK-3β-overexpressing (GSK-3β-OE) mice. In the former, aging was associated with a layer-specific reorganization, characterized by progressive astrocyte loss in the SGZ, midlife increases in GCL microglia, a reduction in oligodendroglial progenitors, and enhanced SGZ vascularization. GSK-3β overexpression accelerated age-related changes, triggering premature SGZ astrocyte depletion by 4 months, broader disruption featuring reduced SGZ microglial and mature oligodendrocyte densities accompanied by increased microglial morphological complexity, vascular restructuring, and a shift toward a pro-inflammatory environment. Therefore, neuronal GSK-3β overexpression promoted a non-cell-autonomous reorganization of the DG, consistent with premature remodeling of the neurogenic niche. These results provide mechanistic insights into AHN failure in AD and point to the modulation of GSK-3β activity as a strategy to preserve DG integrity.
SN - 0894-1491
SN - 1098-1136
ER -