Targeting the BACE1-GSK-3β Signaling Axis in Alzheimer's Disease: From Molecular Crosstalk to Nanotechnology-Based Translational Strategies.

Recent evidence demonstrates that the interplay of amyloidogenesis and tauopathy plays a significant role in exacerbating neurodegeneration in Alzheimer's disease. This interplay of molecular pathways aids in the formation and accumulation of amyloid beta and neurofibrillary tangles extracellularly and intracellularly, respectively. These interconnected pathways highlight the need for the simultaneous inhibition of BACE1 and GSK-3β for the mitigation of disease progression. There are several drugs developed against BACE1 and GSK-3β separately, but they have limited therapeutic efficacy and failed in clinical trials. The failure is due to systemic toxicity and off-target side effects, limited blood-brain barrier permeation, and lower therapeutic benefits. Advances in brain-targeted drug delivery approaches aim to provide site-specific drug delivery, co-delivery of dual drugs, and enhanced stability. Nanoformulations such as lipid-based nanoparticles, polymeric nanoparticles, and hybrid nanoformulations with surface functionalization demonstrate better results in pre-clinical studies. Various research studies have established that targeting amyloidogenesis and tau hyperphosphorylation pathways is a promising therapeutic approach for attenuating neurodegeneration, with the integration of nanotechnology. This review article provides insights into the interplay of BACE1 and GSK-3β molecular signaling pathways, examines the limitations of conventional therapies, and highlights the potential of dual-targeting nanoformulations, while emphasizing the challenges of clinical translation and effective therapeutic strategies to overcome these and treat AD.