Targeting glycogen synthase kinase-3β for Alzheimer's disease: Recent advances and future Prospects

Senile plaques induced by β-amyloid (Aβ) abnormal aggregation and neurofibrillary tangles (NFT) caused by tau hyperphosphorylation are important pathological manifestations of Alzheimer's disease (AD). Glycogen synthase kinase-3 (GSK-3) is a conserved kinase; one member GSK-3β is highly expressed in the AD brain and involved in the formation of NFT. Hence, pharmacologically inhibiting GSK-3β activity and expression is a good approach to treat AD. As summarized in this article, multiple GSK-3β inhibitors has been comprehensively summarized over recent five years. However, only lithium carbonate and Tideglusib have been studied in clinical trials of AD. Besides ATP-competitive and non-ATP-competitive inhibitors, peptide inhibitors, allosteric inhibitors and other types of inhibitors have gradually attracted more interest. Moreover, considering the close relationship between GSK-3β and other targets involved in cholinergic hypothesis, Aβ aggregation hypothesis, tau hyperphosphorylation hypothesis, oxidative stress hypothesis, neuro-inflammation hypothesis, etc., diverse multifunctional molecules and multi-target directed ligands (MTDLs) have also been disclosed. We hope that these recent advances and critical perspectives will facilitate the discovery of safe and effective GSK-3β inhibitors for AD treatment.