Glycogen Synthase Kinase-3β Inhibition Ameliorates Synaptic and Mitochondrial Dysfunction in a Sporadic Alzheimer's Disease-Like Model.

Authors

Ya-Han Wang, Peng-Li Ding, Hao Qin, Kai-Xin Zhang, Jin-Wen Ge, Da-Hua Wu, Le Xie, Kun Liang

Published in

Molecular neurobiology. Volume 63. Issue 1. Jun 17, 2026. Epub Jun 17, 2026.

Abstract

Abnormal glucose metabolism in the central nervous system is a major cause of sporadic Alzheimer's disease (SAD). We hypothesize that glycogen synthase kinase 3β (GSK3β) mediates cognitive impairment by inhibiting the Wnt/β-catenin pathway, which in turn induces abnormal glucose metabolism, synaptic damage, and mitochondrial dysfunction. To test this hypothesis, we injected streptozotocin bilaterally into the lateral ventricles of 100 male C57BL/6 J mice to establish in vivo models of SAD, and into HT22 cells to establish in vitro models of SAD. GSK3β expression was knocked down via adeno-associated virus (AAV) injection into the hippocampal CA1 region in vivo and via lentiviral transfection in vitro. We assessed cognitive function using the Morris water maze, Y-maze, and novel object recognition tests (n = 10). Glucose metabolism was evaluated by 18F-FDG PET imaging (n = 3), while synaptic and myelin sheath ultrastructure was examined using transmission electron microscopy (n = 6). Cell viability, mitochondrial function, and key protein expression were measured using CCK-8 assays, Seahorse analysis, and molecular biology techniques, respectively (n = 3, n = 6). In both in vivo and in vitro STZ-induced SAD models, GSK3β knockdown significantly reduced amyloid-β (1-42) deposition and tau hyperphosphorylation, activated the Wnt/β-catenin pathway, enhanced glucose metabolism, reversed glycolytic inhibition and mitochondrial dysfunction, and repaired synaptic and myelin sheath damage, ultimately improving cognitive deficits. Our findings demonstrate that GSK3β knockdown ameliorates STZ-induced SAD-like pathologies by restoring Wnt/β-catenin signaling and normalizing glucose metabolism, highlighting GSK3β as a potential therapeutic target for SAD.

PMID:
42307791
Bibliographic data and abstract were imported from PubMed on 17 Jun 2026.

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