GSK3β knockdown reverses synaptic and mitochondrial dysfunction, improving cognition in sporadic Alzheimer's disease models

Abnormal glucose metabolism in the central nervous system is a primary driver of sporadic Alzheimer's disease (SAD), a progressive neurodegenerative condition characterized by cognitive impairment and neuronal loss. Current treatments often fall short in addressing the multifaceted pathology. This study investigates glycogen synthase kinase 3β (GSK3β), hypothesizing it mediates cognitive decline by inhibiting the Wnt/β-catenin pathway, leading to glucose hypometabolism, synaptic damage, and mitochondrial dysfunction, which are key features of AD progression.

Researchers established in vivo SAD models by bilaterally injecting streptozotocin (STZ) into the lateral ventricles of 100 male C57BL/6J mice. In vitro models used STZ-treated HT22 cells. To inhibit GSK3β, adeno-associated virus (AAV) was injected into the hippocampal CA1 region in vivo, while lentiviral transfection was used in vitro. Cognitive function was assessed using Morris water maze, Y-maze, and novel object recognition tests (n=10). Glucose metabolism was evaluated by 18F-FDG PET imaging (n=3). Synaptic and myelin sheath ultrastructure was examined via 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 (n=3, n=6 respectively).

In both STZ-induced in vivo and in vitro SAD models, GSK3β knockdown consistently demonstrated significant therapeutic effects. It significantly reduced amyloid-β (1-42) deposition and tau hyperphosphorylation, two hallmarks of AD pathology. The intervention also activated the Wnt/β-catenin pathway, which is crucial for neuronal health and plasticity. Furthermore, GSK3β knockdown enhanced glucose metabolism and reversed glycolytic inhibition, addressing a core metabolic deficit in SAD. Mitochondrial dysfunction, a critical factor in neurodegeneration, was also reversed. Synaptic and myelin sheath damage, essential for proper neuronal communication, was repaired. Ultimately, these cellular and metabolic improvements translated into improved cognitive deficits in the animal models.

GSK3β knockdown ameliorated STZ-induced SAD-like pathologies by restoring Wnt/β-catenin signaling and normalizing glucose metabolism, highlighting GSK3β as a potential therapeutic target for SAD.