C-Glycosylflavones Alleviate Tau Phosphorylation and Amyloid Neurotoxicity through GSK3β 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-3β (GSK3β) is a key kinase responsible for tau hyperphosphorylation. Selective inhibition of GSK3β 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 GSK3β 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 GSK3β in vitro. Enzyme kinetics and molecular docking studies demonstrated that 1 specifically inhibited GSK3β via an ATP noncompetitive mechanism, acting as a substrate competitive inhibitor of GSK3β. Further in vitro cellular studies demonstrated that 1 effectively attenuated tau phosphorylation mediated by GSK3β and was neuroprotective against β-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.

Melatonin ameliorates Aβ42‐induced alteration of βAPP‐processing secretases via the melatonin receptor through the Pin1/GSK3β/NF‐κB pathway in SH‐SY5Y cells

“…GSK3β is an imperative regulator of amyloidogenic processing of βAPP and tau hyperphosphorylation, and its inhibition reduces Aβ and tau pathology . In this context, our results first demonstrated that Aβ 42 activated GSK3β by decreasing its phosphorylation, which was prevented by melatonin pretreatments in a receptor‐dependent manner.…”

“…59,60 GSK3β is an imperative regulator of amyloidogenic processing of βAPP and tau hyperphosphorylation, 14,61 and its inhibition reduces Aβ 15 and tau pathology. 16 In this context, our results first demonstrated that Aβ 42 activated GSK3β by decreasing its phosphorylation, which was prevented by melatonin pretreatments in a receptor-dependent manner. Because alterations in GSK3β activity could lead to changes in PS1 function [62][63][64] and GSK3β is also involved in regulating BACE1 15 and NF-κB activity, 65 using ARA (GSK3β inhibitor) data justified GSK3β-dependent regulation of BACE1 and PS1 under pathological conditions because blocking GSK3β resulted in partial inhibition of the Aβ 42 -induced increase in the levels of BACE1 and PS1 as well as the Aβ 42induced upregulation of pNF-κB/NF-κB.…”

LC/QTOF profile and preliminary stability studies of an enriched flavonoid fraction of Cecropia pachystachya Trécul leaves with potential antidepressant‐like activity

“…The flavonoid activities in the central nervous system have been previously reported in the literature (Grosso, Valentão, Ferreres, & Andrade, ). Liang, Zhang, Su, Williams, and Li () described the C‐ glycosyl flavones as a possibility of new lead candidates with a novel mechanism of action for the development of Alzheimer's disease. The antidepressant‐like effects of C‐ glycosyl flavonoids were described for vitexin, underlying its monoaminergic mechanisms (Can, DemirÖzkay, & Üçel, ); and for orientin, with improvement of central oxidative stress, neurotransmission and neuroplasticity (Liu et al, ).…”

“…In fact, the The flavonoid activities in the central nervous system have been previously reported in the literature (Grosso, Valentão, Ferreres, & Andrade, 2013). Liang, Zhang, Su, Williams, and Li (2016) described the C-glycosyl flavones as a possibility of new lead candidates with a novel mechanism of action for the development of Alzheimer's disease.…”

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

“…In this section, CADD techniques employed for the development of anti-Tau therapeutics are summarized. Molecular docking and enzymatic kinetics demonstrated that C-glycosylflavones selectively inhibited GSK3β-mediated Tau hyperphosphorylation acting as a substrate competitive inhibitor [148]. A group of marine indole alkaloids isolated from the marine tunicate Aplidium were identified as scaffolds for designing new anti-Tau hyperphosphorylation inhibitors using docking and MD simulations [149].…”