Decoding the Role of Neurotrophins in Glycogen Synthase Kinase 3-Beta Regulation in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most prevalent contributor to dementia in elderly individuals. Numerous signalling pathways influencing AD pathophysiology, involving glycogen synthase kinase-3β (Gsk-3β), have been investigated extensively as potential therapeutic targets. Gsk-3β is a critical factor in AD pathogenesis that affects several key hallmarks of the disease notably tau phosphorylation, amyloid-β generation, cognition, neurogenesis, and synaptic integrity. Neurotrophins are small proteins that are critical for maintaining neuronal health and function and may be used to treat neurodegenerative diseases. Notably, the dysregulation of certain neurotrophins and their receptors is also linked with AD which is a major contributor to neurodegeneration. Studies indicated that neurotrophins and their modulators are capable of protecting neurons by blocking the Gsk-3β activity suggesting a potential link for neuroprotection. Neurotrophins support the survival of neurons by regulating Gsk-3β activity. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) signalling pathways activate Trk receptors that trigger downstream signalling cascades that subsequently inhibit Gsk-3β activity and reduce AD-related neuropathology. We also explore the role of modulators including phosphatases, kinase cascades, and other regulatory proteins that cross paths with neurotrophin-Gsk-3β signalling. In conclusion, this manuscript summarizes both direct and indirect regulatory roles of neurotrophins and modulators on Gsk-3β to understand the intricate mechanisms driving neurodegeneration in AD.