Geon Targeting Truncation-activated GSK-3β to Beat Alzheimer's Disease

 

Abstract

Excessive activation of glycogen synthase kinase-3β (GSK-3β) can cause not only Tau pathology, but also amyloid plaques. Thus, GSK-3β should be a promising therapeutic target for the treatment of Alzheimer's disease (AD). GSK-3β can be activated by either dephosphorylation at Ser9 via reduced Akt activity or truncation via calpain activation. Curcumin and Tideglusib are potent inhibitors of the full-length GSK-3β (IC50 ~ 60 nM), but they did not produce clinical benefits. Lithium is a weak GSK-3β inhibitor, with IC50 around 3 mM. Yet, clinical studies supported the effects of lithium for dementia prevention. Strikingly, lithium has been demonstrated to inhibit both dephosphorylation- and truncation-activated GSK-3β with the same IC50. These findings suggest that in AD hyperactive GSK-3β could arise primarily from truncation that cannot be inhibited by curcumin and Tideglusib. Although lithium exhibits benefits for dementia prevention, its potency and selectivity are insufficient for the treatment of AD. Potent and selective inhibitors of truncation-activated GSK-3β hold promise to beat Alzheimer's disease.

 

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