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

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 patholo...

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Main Authors:	Xiao-Long Shi, Ning Yan, Ying-Jie Cui, Zhao-Peng Liu
Format:	Article
Language:	English
Published:	MDPI AG 2020-03-01
Series:	Cells
Subjects:	alzheimer’s disease aβ gsk-3β inhibitor tau metal dyshomeostasis neurite outgrowth
Online Access:	https://www.mdpi.com/2073-4409/9/3/649

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spelling	doaj-48e13760299849e79222c447ca1667612020-11-25T02:15:07ZengMDPI AGCells2073-44092020-03-019364910.3390/cells9030649cells9030649A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite OutgrowthXiao-Long Shi0Ning Yan1Ying-Jie Cui2Zhao-Peng Liu3Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, ChinaKey Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, ChinaDue 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.https://www.mdpi.com/2073-4409/9/3/649alzheimer’s diseaseaβgsk-3β inhibitortaumetal dyshomeostasisneurite outgrowth
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Xiao-Long Shi Ning Yan Ying-Jie Cui Zhao-Peng Liu
spellingShingle	Xiao-Long Shi Ning Yan Ying-Jie Cui Zhao-Peng Liu A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth Cells alzheimer’s disease aβ gsk-3β inhibitor tau metal dyshomeostasis neurite outgrowth
author_facet	Xiao-Long Shi Ning Yan Ying-Jie Cui Zhao-Peng Liu
author_sort	Xiao-Long Shi
title	A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth
title_short	A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth
title_full	A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth
title_fullStr	A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth
title_full_unstemmed	A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth
title_sort	unique gsk-3β inhibitor b10 has a direct effect on aβ, targets tau and metal dyshomeostasis, and promotes neuronal neurite outgrowth
publisher	MDPI AG
series	Cells
issn	2073-4409
publishDate	2020-03-01
description	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.
topic	alzheimer’s disease aβ gsk-3β inhibitor tau metal dyshomeostasis neurite outgrowth
url	https://www.mdpi.com/2073-4409/9/3/649
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A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth

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