Pharmacological modulation of the PI3K/AKT/GSK3β axis: a new frontier in Alzheimer's disease treatment

Amyloid-beta (Aβ) plaques and the intracellular buildup of hyperphosphorylated tau protein are hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease that causes synaptic dysfunction and neuronal death. Glycogen synthase kinase 3 beta (GSK3β), protein kinase B (AKT), and phosphatidylinositol 3-kinase all have aberrant signaling pathways that contribute to the pathophysiology of AD. The PI3K/AKT neuroprotective pathway is seriously inhibited in AD, which leads to brain insulin resistance (BIR) and neurodegeneration. However, AD leads to hyperactivation of GSK3β, which in turn produces tau hyperphosphorylation, Aβ accumulation, and cognitive impairment. BIR and PI3K/AKT/GSK3β signaling in AD have a complicated interaction that is covered in this article. The pathway has both neuroprotective and pathogenic functions. The therapeutic use of GSK3β inhibitors and PI3K/AKT activators to decrease AD pathogenesis is also discussed. Changing these pathways can improve cognitive function, reduce tau and Aβ pathology, and restore insulin signaling, according to preclinical and clinical research. Finding highly specialized treatments with minimal side effects remains a challenge. More research is required to thoroughly assess the safety and efficacy of medications that target specific pathways and to clarify the molecular mechanisms underlying PI3K/AKT/GSK3β dysregulation in AD in order to create novel and effective treatment alternatives.