Unlocking hope: GSK-3 inhibitors and Wnt pathway activation in Alzheimer's therapy.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterised by progressive cognitive decline and the accumulation of amyloid-ß plaques and tau tangles. The Wnt signalling pathway known for its crucial role in neurodevelopment and adult neurogenesis has emerged as a potential target for therapeutic intervention in AD. Glycogen synthase kinase-3 beta (GSK-3ß), a key regulator of the Wnt pathway, plays a pivotal role in AD pathogenesis by promoting tau hyperphosphorylation and neuroinflammation. Several preclinical studies have demonstrated that inhibiting GSK-3ß leads to the activation of Wnt pathway thereby promoting neuroprotective effects, and mitigating cognitive deficits in AD animal models. The modulation of Wnt signalling appears to have multifaceted benefits including the reduction of amyloid-ß production, tau hyperphosphorylation, enhancement of synaptic plasticity, and inhibition of neuroinflammation. These findings suggest that targeting GSK-3ß to activate Wnt pathway may represent a novel approach for slowing or halting the progression of AD. This hypothesis reviews the current state of research exploring the activation of Wnt pathway through the inhibition of GSK-3ß as a promising therapeutic strategy in AD.

Rational Design of Dual Inhibitors for Alzheimer's Disease: Insights from Computational Screening of BACE1 and GSK-3ß.

BACKGROUND: Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aß and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3ß, two proteins implicated in Aß and NFT formation respectively. METHODS: We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3ß. RESULTS: Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3ß over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3ß. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies. CONCLUSION: Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration.