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

Cells
Xiao-Long ShiZhao-Peng Liu

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-3β (GSK-3β) 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-3β inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3β with an IC50 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 Aβ1-42 aggregation and promoting the Aβ1-42 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 outgro...Continue Reading

References

Jul 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·I Grundke-IqbalL I Binder
May 9, 1997·The Journal of Biological Chemistry·L O TjernbergC Nordstedt
Aug 18, 1999·Journal of Chemical Neuroanatomy·K Leroy, J P Brion
Aug 31, 2001·Progress in Neurobiology·C A Grimes, R S Jope
Dec 21, 2004·Nature Neuroscience·James P ClearyKaren H Ashe
Aug 18, 2006·Journal of Alzheimer's Disease : JAD·John Hardy
Aug 18, 2006·Journal of Alzheimer's Disease : JAD·Akihiko Takashima
Dec 20, 2007·Journal of Neurochemistry·Claudie HooperSimon Lovestone
Apr 10, 2009·Current Alzheimer Research·Giancarlo Pepeu, Maria Grazia Giovannini
Jan 25, 2011·Trends in Pharmacological Sciences·Alan M Palmer
Feb 8, 2011·Behavioural Brain Research·E A Van der ZeeG Riedel
Mar 12, 2011·Neuroscience and Biobehavioral Reviews·Laura A CraigRobert J McDonald
Jul 22, 2011·International Journal of Alzheimer's Disease·Diane P Hanger, Wendy Noble
Jul 28, 2011·Medicinal Research Reviews·Rafael LeónJosé Marco-Contelles
Nov 24, 2011·Frontiers in Molecular Neuroscience·Raquel Gómez-SintesJesús Avila
Jul 17, 2012·Chemical Reviews·Kasper P Kepp
Sep 18, 2012·Neurochemistry International·Mark A GreenoughAshley I Bush
Nov 13, 2012·Free Radical Biology & Medicine·Scott AytonAshley I Bush
Nov 28, 2012·Chemistry : a European Journal·Peter Faller, Christelle Hureau
Jul 8, 2015·Neuropeptides·Sagar H Barage, Kailas D Sonawane
Aug 2, 2015·Archivum Immunologiae Et Therapiae Experimentalis·Zhi-Gang ZhangYou-Qiang Song
Oct 24, 2015·Brain Pathology·Ramesh KandimallaKiran Dip Gill
Nov 13, 2015·European Journal of Medicinal Chemistry·Mudasir MaqboolNasimul Hoda
Jan 2, 2016·Pharmacological Reports : PR·Justyna GodyńBarbara Malawska
Mar 31, 2016·EMBO Molecular Medicine·Dennis J Selkoe, John Hardy
Apr 29, 2016·Biomedical Reports·Wen-Juan HuangWei-Wei Chen
Oct 19, 2016·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·David M HoltzmanMichael Hutton
Jun 19, 2016·Brain Research Bulletin·A TramutolaD Allan Butterfield

❮ Previous
Next ❯

Citations

Oct 21, 2020·Biomedicines·Adrian Florian BălașaAlexandru Mihai Grumezescu
Nov 19, 2020·Brain Sciences·Antonio Dominguez-MeijideTiago Fleming Outeiro
Nov 22, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zheng LiuCheng-Xi Wei

❮ Previous
Next ❯

Methods Mentioned

BETA
Fluorescence
electrophoresis
transmission electron microscopy
Assay
Reverse Transcription-PCR
transgenic
ubiquitination

Software Mentioned

Pro32
GraphPad
SYBYL
GraphPad Prism
Gel
XLfit
Surflex
Excel
X suite
AMBER7

Related Concepts

Related Feeds

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.

Alzheimer's Disease: Tau & TDP-43

Alzheimer's disease is a neurodegenerative disease. This feed focuses on the underlying role of tau proteins and TAR DNA-binding protein 43, as well as other genetic factors, in Alzheimer's disease.