Work

Neuronal Overexpression of Glycogen Synthase Kinase‐3β Accelerates Age‐Related Glial, Vascular, and Inflammatory Remodeling of the Murine Dentate Gyrus

Year: 2026

Type: article

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.

Source: Glia

DOI: 10.1002/glia.70248

Authors: Ana V. Prádanos‐Senén, Carla B. Rodríguez‐Moreno, María Llorens‐Martín

Institutions: Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Biomedical Research Networking Center on Neurodegenerative Diseases

Language: English

Topic: Neurogenesis and neuroplasticity mechanisms

Subfield: Developmental Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,450