Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein

The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal re...

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Autores principales:	Gaoping Lin, Feiyan Zhu, Nicholas M. Kanaan, Rei Asano, Norimichi Shirafuji, Hirohito Sasaki, Tomohisa Yamaguchi, Soichi Enomoto, Yoshinori Endo, Asako Ueno, Masamichi Ikawa, Kouji Hayashi, Osamu Yamamura, Shu-Hui Yen, Yasunari Nakamoto, Tadanori Hamano
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Alzheimer’s disease clioquinol tau protein tau oligomer JNK PP2A Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/772bb6631d544c91a2e45d58ccfa195e
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spelling	oai:doaj.org-article:772bb6631d544c91a2e45d58ccfa195e2021-11-11T17:27:37ZClioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein10.3390/ijms2221120631422-00671661-6596https://doaj.org/article/772bb6631d544c91a2e45d58ccfa195e2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12063https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn<sup>2+</sup> and Cu<sup>2+</sup>, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu<sup>2+</sup> induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu<sup>+</sup> in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.Gaoping LinFeiyan ZhuNicholas M. KanaanRei AsanoNorimichi ShirafujiHirohito SasakiTomohisa YamaguchiSoichi EnomotoYoshinori EndoAsako UenoMasamichi IkawaKouji HayashiOsamu YamamuraShu-Hui YenYasunari NakamotoTadanori HamanoMDPI AGarticleAlzheimer’s diseaseclioquinoltau proteintau oligomerJNKPP2ABiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12063, p 12063 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s disease clioquinol tau protein tau oligomer JNK PP2A Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Alzheimer’s disease clioquinol tau protein tau oligomer JNK PP2A Biology (General) QH301-705.5 Chemistry QD1-999 Gaoping Lin Feiyan Zhu Nicholas M. Kanaan Rei Asano Norimichi Shirafuji Hirohito Sasaki Tomohisa Yamaguchi Soichi Enomoto Yoshinori Endo Asako Ueno Masamichi Ikawa Kouji Hayashi Osamu Yamamura Shu-Hui Yen Yasunari Nakamoto Tadanori Hamano Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein
description	The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn<sup>2+</sup> and Cu<sup>2+</sup>, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu<sup>2+</sup> induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu<sup>+</sup> in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.
format	article
author	Gaoping Lin Feiyan Zhu Nicholas M. Kanaan Rei Asano Norimichi Shirafuji Hirohito Sasaki Tomohisa Yamaguchi Soichi Enomoto Yoshinori Endo Asako Ueno Masamichi Ikawa Kouji Hayashi Osamu Yamamura Shu-Hui Yen Yasunari Nakamoto Tadanori Hamano
author_facet	Gaoping Lin Feiyan Zhu Nicholas M. Kanaan Rei Asano Norimichi Shirafuji Hirohito Sasaki Tomohisa Yamaguchi Soichi Enomoto Yoshinori Endo Asako Ueno Masamichi Ikawa Kouji Hayashi Osamu Yamamura Shu-Hui Yen Yasunari Nakamoto Tadanori Hamano
author_sort	Gaoping Lin
title	Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein
title_short	Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein
title_full	Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein
title_fullStr	Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein
title_full_unstemmed	Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein
title_sort	clioquinol decreases levels of phosphorylated, truncated, and oligomerized tau protein
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/772bb6631d544c91a2e45d58ccfa195e
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Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein

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