| Summary: | 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-3β (GSK-3β) plays a vital role in the AD pathological process. In this study, we discovered a novel 1<i>H</i>-pyrrolo[2,3-b]pyridine derivative B10 as a GSK-3β inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3β with an IC<sub>50</sub> of 66 ± 2.5 nM. At the concentration of 20 μM, B10 increased β-catenin abundance (β-catenin/GAPDH: 0.83 ± 0.086 vs. 0.30 ± 0.016), phosphorylated GSK-3β at Ser9 (p-GSK-3β/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-3β inhibitors, B10 had a direct effect on Aβ by inhibiting Aβ<sub>1-42</sub> aggregation and promoting the Aβ<sub>1-42</sub> aggregate disassociation. It selectively chelated with Cu<sup>2+</sup>, Zn<sup>2+</sup>, Fe<sup>3+,</sup> and Al<sup>3+</sup>, 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-3β and β-catenin signal pathways. Therefore, B10 is a potent and unique GSK-3β inhibitor that has a direct on Aβ and serves as a multifunctional anti-AD agent for further investigations.
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