{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:03:22Z","timestamp":1788498202090,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T00:00:00Z","timestamp":1636329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI Grant","award":["19K07909"],"award-info":[{"award-number":["19K07909"]}]},{"DOI":"10.13039\/501100014996","name":"health and family planning commission of Zhejiang province","doi-asserted-by":"publisher","award":["2015KYB016"],"award-info":[{"award-number":["2015KYB016"]}],"id":[{"id":"10.13039\/501100014996","id-type":"DOI","asserted-by":"publisher"}]},{"name":"SMON Research Committee supported by the Ministry of Health, Labour and Welfare, Japan","award":["2021"],"award-info":[{"award-number":["2021"]}]},{"name":"Research grant from the University of Fukui","award":["LSI20306"],"award-info":[{"award-number":["LSI20306"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The neuropathological hallmarks of Alzheimer\u2019s disease (AD) are senile plaques (SPs), which are composed of amyloid \u03b2 protein (A\u03b2), 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 Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ 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 \u03bcM CQ had no effect on cell viability; however, 100 \u03bcM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ 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.<\/jats:p>","DOI":"10.3390\/ijms222112063","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T08:05:16Z","timestamp":1636358716000},"page":"12063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein"],"prefix":"10.3390","volume":"22","author":[{"given":"Gaoping","family":"Lin","sequence":"first","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"},{"name":"Department of Neurology, Zhejiang Provincial People\u2019s Hospital, People\u2019s Hospital of Hangzhou Medical College, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiyan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"},{"name":"Department of Neurology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4362-2593","authenticated-orcid":false,"given":"Nicholas M.","family":"Kanaan","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rei","family":"Asano","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norimichi","family":"Shirafuji","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"},{"name":"Department of Aging and Dementia (DAD), Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohito","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohisa","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichi","family":"Enomoto","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"},{"name":"Department of Aging and Dementia (DAD), Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Endo","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asako","family":"Ueno","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9785-0535","authenticated-orcid":false,"given":"Masamichi","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouji","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Yamamura","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Hui","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunari","family":"Nakamoto","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3492-9585","authenticated-orcid":false,"given":"Tadanori","family":"Hamano","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"},{"name":"Department of Aging and Dementia (DAD), Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan"},{"name":"Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1093\/oxfordjournals.jbchem.a135662","article-title":"Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer\u2019s disease","volume":"99","author":"Ihara","year":"1986","journal-title":"J. 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