Targeting GSK-3β to Modulate the Wnt Pathway: A Promising Neuroprotective Strategy for Alzheimer's Disease

Area of Science:

• Neuroscience
• Nanotechnology
• Pharmacology

Background:

• Alzheimer's disease (AD) is characterized by amyloid-β plaques and neurofibrillary tangles.
• Glycogen synthase kinase-3β (GSK-3β) is a therapeutic target for AD, but non-specific inhibition causes side effects.
• Brain-targeted delivery systems are needed to improve therapeutic efficacy and reduce off-target effects.

Purpose of the Study:

• To develop and characterize polysorbate 80 and stearic acid-modified solid lipid nanoparticles (PS80-SA SLNs) encapsulating indirubin-3 -oxime (IMX) for brain-targeted delivery.
• To evaluate the neuroprotective efficacy and therapeutic potential of PS80-SA SLNs-IMX against Alzheimer's disease pathologies.
• To assess the biodistribution and brain-specific delivery of IMX using the developed nanocarrier system.

Main Methods:

• PS80-SA SLNs-IMX were prepared using the solvent injection method and optimized via full factorial design.
• Formulations were characterized for particle size, polydispersity index, zeta potential, morphology, and drug entrapment efficiency.
• In vitro neuroprotection was assessed using cell lines, and in vivo biodistribution was studied in Wistar rats.
• Biochemical assays (ELISA, Western blot) were used to evaluate the modulation of AD biomarkers and signaling pathways.

Main Results:

• Optimized PS80-SA SLNs-IMX exhibited favorable physicochemical properties: particle size (185.7 nm), PDI (0.22), zeta potential (-21.02 mV), and high entrapment efficiency (99.4%).
• The formulation demonstrated sustained drug release up to 48 hours, good stability, and negligible cytotoxicity.
• In vitro studies showed significant antioxidant and neuroprotective effects against okadaic acid (OKA)-induced neurotoxicity, reducing Aβ1-42 and p-tau levels.
• Biodistribution studies confirmed enhanced brain concentration of IMX delivered via PS80-SA SLNs-IMX compared to free IMX.

Conclusions:

• PS80-SA SLNs-IMX effectively delivers IMX to the brain, demonstrating significant neuroprotective and antioxidant properties in vitro.
• The formulation successfully inhibited GSK-3β, modulated the Wnt pathway, and reduced key AD biomarkers (Aβ1-42, p-tau).
• This study presents the first report of PS80-SA SLNs-IMX with high entrapment and robust neuroprotection in an OKA-induced tauopathy model, highlighting its translational potential for Alzheimer's disease therapy.