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

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. Graphical The alternative text for this image may have been generated using AI.