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

• Published in: Journal of drug targeting 2024-09, Vol.32 (8), p.1-917
• Main Authors: Sai Varshini, Magham, Aishwarya Reddy, Ramakkamma, Thaggikuppe Krishnamurthy, Praveen
• Format: Article
• Language: English
• ISSN: 1061-186X; 1029-2330; 1029-2330
• DOI: 10.1080/1061186X.2024.2365263

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterised by progressive cognitive decline and the accumulation of amyloid-β 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-3β), 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-3β 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-β production, tau hyperphosphorylation, enhancement of synaptic plasticity, and inhibition of neuroinflammation. These findings suggest that targeting GSK-3β 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-3β as a promising therapeutic strategy in AD.