PMID: 32155989

A Unique GSK-3beta inhibitor B10 Has a Direct Effect on Abeta, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth.

Abstract

Due to the complicated pathogenesis of Alzheimer's disease (AD), the development of multitargeted agents to simultaneously interfere with multiple pathological processes of AD is a potential choice. Glycogen synthase kinase-3beta (GSK-3beta) plays a vital role in the AD pathological process. In this study, we discovered a novel 1H-pyrrolo[2,3-b]pyridine derivative B10 as a GSK-3beta inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3beta with an IC(50) of 66 +/- 2.5 nM. At the concentration of 20 muM, B10 increased beta-catenin abundance (beta-catenin/GAPDH: 0.83 +/- 0.086 vs. 0.30 +/- 0.016), phosphorylated GSK-3beta at Ser9 (p-GSK-3beta/GAPDH: 0.53 +/- 0.045 vs. 0.35 +/- 0.012), and decreased the phosphorylated tau level (p-tau/GAPDH: 0.33 +/- 0.065 vs. 0.83 +/- 0.061) in SH-SY5Y cells. Unlike other GSK-3beta inhibitors, B10 had a direct effect on Abeta by inhibiting Abeta(1-42) aggregation and promoting the Abeta(1-42) aggregate disassociation. It selectively chelated with Cu(2+), Zn(2+), Fe(3+,) and Al(3+), and targeted AD metal dyshomeostasis. Moreover, B10 effectively increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth, possibly through the GSK-3beta and beta-catenin signal pathways. Therefore, B10 is a potent and unique GSK-3beta inhibitor that has a direct on Abeta and serves as a multifunctional anti-AD agent for further investigations.