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

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.