A Unique GSK-3ß inhibitor B10 Has a Direct Effect on Aß, 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-3ß (GSK-3ß) 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-3ß inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3ß with an IC50 of 66 ± 2.5 nM. At the concentration of 20 µM, B10 increased ß-catenin abundance (ß-catenin/GAPDH 0.83 ± 0.086 vs. 0.30 ± 0.016), phosphorylated GSK-3ß at Ser9 (p-GSK-3ß/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-3ß inhibitors, B10 had a direct effect on Aß by inhibiting Aß1-42 aggregation and promoting the Aß1-42 aggregate disassociation. It selectively chelated with Cu2+, Zn2+, Fe3+, and Al3+, 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-3ß and ß-catenin signal pathways. Therefore, B10 is a potent and unique GSK-3ß inhibitor that has a direct on Aß and serves as a multifunctional anti-AD agent for further investigations.