ArticleFrontiers in neuroscience2025
Spatiotemporal differential regulation of extrasynaptic GluN2B receptor subunits and PSA-NCAM in brain aging and Alzheimer's disease.
Article in Frontiers in neuroscience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Polysialic Acid Modulation of Glutamate Receptors and Synaptic Mechanisms Underlying Neuronal Plasticity.NeuroSci · 2026Review
- Molecular interplay between glycogen synthase kinase 3 beta and A-kinase anchoring protein 11 in bipolar disorder: a narrative review.Frontiers in molecular neuroscience · 2026Review
- Standardized protocol for plasticity assessment in the aging mouse neocortex using choline-chloride perfusion.Frontiers in aging neuroscience · 2026Article
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7 authors.
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Abstract
Introduction: Extrasynaptic GluN2B N-methyl-D-aspartate receptors (ES-GluN2B) are localized outside synapses and promote excitotoxic signaling, apoptosis, and long-term depression (LTD) in Alzheimer's disease (AD). Polysialylated neural cell adhesion molecule (PSA-NCAM) physiologically inhibits ES-GluN2B activity, and its downregulation is associated with impaired synaptic plasticity. However, the spatiotemporal changes of ES-GluN2B and PSA-NCAM during brain aging versus AD remain poorly understood. Methods: We investigated GluN2A, GluN2B, ES-GluN2B, and PSA-NCAM expression across brain regions in young and old Tg2576 AD and wild-type (WT) mice. Additional experiments included PSD-95 pulldown assays, analysis of GluN2B phosphorylation at Ser1480, CRISPRa-driven ST8Sia4 upregulation in IMR-32 neuroblastoma cells, and Aβ treatment to assess effects on PSA-NCAM biosynthetic enzymes. Results: Normal aging was associated with decreased GluN2B, increased GluN2A, stable ES-GluN2B, and elevated PSA-NCAM levels. In contrast, AD aging showed elevated ES-GluN2B and reduced PSA-NCAM, particularly in the hippocampus and cortex, with no change in total NCAM expression. PSD-95 pulldown revealed increased extrasynaptic GluN2B in aged AD brains. AD aging was associated with elevated phosphorylation of GluN2B at Ser1480 by casein kinase 2 (CK2), promoting GluN2B redistribution to extrasynaptic sites. CRISPRa-driven ST8Sia4 upregulation increased PSA-NCAM and reduced pGluN2B expression supporting a direct regulatory role for PSA-NCAM in GluN2B trafficking. Additionally, Aβ suppressed PSA-NCAM biosynthetic enzymes ST8Sia4 and UDP-E linking Aβ to impaired polysialylation. Discussion: These findings highlight distinct regulatory patterns of ES-GluN2B and PSA-NCAM in AD versus normal aging and support a model in which impaired PSA-NCAM buffering facilitates pathological ES-GluN2B signaling and plasticity loss in AD progression.
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