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GSK-3 and CNS


Dysregulation of GSK-3 activity is believed to play a key role in the pathogenesis of CNS disorders. GSK-3 and its downstream pathways were shown to be tightly linked with signaling pathways regulating synaptic modulation, neuroprotection and neuroplasticity. Of particular relevance to neurodegenarative disorders, GSK-3 binds and / or phosphoryltes tau, presenilin-1, and collapsin response mediator protein, CRMP2, proteins that are implicated in the etiology of Alzheimer’s disease. Specifically, GSK-3 phosphorylates tau in most serine and threonine residues which are hyperphosphorylated in PHF (paired helical filament) in brains of Alzheimer’s patients. Subsequently, the phosphorylation of CRMP2 by GSK-3 affects neuroplasticity and axon grwoth. In addition, GSK-3 activity contributes to the production of Aβ peptide, the principal protein component of amyloid plaques, the hallmark of Alzheimer’s disease pathology. Furthermore, recent work suggested a mechanistic link between amyloid signaling and tauopathy via activation of GSK-3.














GSK-3 in CNS and affective disorders

GSK-3 and CNS


Another important aspect in this regard is the contribution of GSK-3 to both inflammation and cell migration. Supportive evidence was also obtained from in vivo models. Thus, mice with conditional overexpression of brain-GSK-3 displayed hyperphosphorylation of tau, apoptotic neuronal cell death, and spatial learning deficit. On the other hand, reduced GSK-3 activity achieved either by pharmacological inhibitors or by genetic manipulations enhanced LTP (long term potentiation) and reversed the Alzheimer’s-like phenotype in vivo. These combined observations strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in Alzheimer’s disease pathology, and possibly in additional neurodegenerative disorders in which neuronal plasticity, cell migration, and/or LTP are hampered.

Learn more about GSK3 in Neuronal Plasticity and Neurodegeneration at Neuro.GSK-3 website.

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