C-Glycosylflavones Alleviate Tau Phosphorylation and Amyloid Neurotoxicity through GSK3? Inhibition.

ABSTRACT: Alzheimer's disease (AD) is the most common brain disorder worldwide. Aberrant tau hyperphosphorylation and accumulation play critical roles in the formation of neurofibrillary tangles highly associated with neuronal dysfunction and cognitive impairment in AD pathogenesis. Glycogen synthase kinase-3? (GSK3?) is a key kinase responsible for tau hyperphosphorylation. Selective inhibition of GSK3? is a promising strategy in AD therapy. Corn silks (CS, Zea mays L.) have been traditionally used as a medicinal herb and recently noted for their potentially cognitive benefits. However, the neuroprotective components of CS and their molecular mechanism have received little attention to date. As part of our effort screening phytochemicals against a broad panel of kinases targeting AD tauopathy, we found inhibition of GSK3? by CS extracts. Subsequent bioassay-guided fractionation led to the isolation and identification of two 6-C-glycosylflavones, isoorientin (1) and 3'-methoxymaysin (2), with selective inhibition against GSK3? in vitro. Enzyme kinetics and molecular docking studies demonstrated that 1 specifically inhibited GSK3? via an ATP noncompetitive mechanism, acting as a substrate competitive inhibitor of GSK3?. Further in vitro cellular studies demonstrated that 1 effectively attenuated tau phosphorylation mediated by GSK3? and was neuroprotective against ?-amyloid-induced tau hyperphosphorylation and neurotoxicity in SH-SY5Y cells. The C-glycosylflavones represent new lead candidates with a novel mechanism of action for the development of AD phytopharmaceuticals.

SUBMITTER: Liang Z 

PROVIDER: S-EPMC7355085 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature