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However, the reason elevated plasma homocysteinemia increases the risk of dementia remains unknown. A pathological hallmark of AD is neurofibrillary tangles (NFTs) that consist of pathologically phosphorylated tau proteins. The effect of homocysteine (Hcy) on tau aggregation was explored using human neuroblastoma M1C cells that constitutively express human wild-type tau (4R0N) under the control of a tetracycline off system, primary mouse cultured neurons, and by inducing hyperhomocysteinemia in a mouse model of tauopathy (HHCy mice). A wide range of Hcy concentrations (10\u20131000 \u00b5M) increased total tau and phosphorylated tau protein levels. Hcy activated glycogen synthase kinase 3, and cyclin dependent kinase 5, major tau phosphokinases, and inactivated protein phosphatase 2A, a main tau phosphatase. Hcy exhibited cytotoxic effects associated with enhanced activation of caspase. Truncation of tau in the C-terminus, the cleavage site of caspase 3 (i.e., D421, detected by the TauC3 antibody) was also increased. Total tau, phosphorylated tau, as well as C-terminal cleaved tau were increased in the sarkosyl insoluble tau fraction. Hcy also increased the level of tau oligomers, as indicated by the tau oligomer complex 1 (TOC1) antibody that specifically identifies oligomeric tau species, in the tris insoluble, sarkosyl soluble fraction. The levels of TOC1-positive oligomeric tau were increased in brain lysates from HHCy mice, and treating HHCy mice with S-adenosylmethionine, an intermediate of Hcy, reduced the levels of oligomeric tau to control levels. These observations suggest that Hcy increases the levels of phosphorylated tau as well as truncated tau species via caspase 3 activation, and enhanced tau oligomerization and aggregation.<\/jats:p>","DOI":"10.3390\/ijms19030891","type":"journal-article","created":{"date-parts":[[2018,3,20]],"date-time":"2018-03-20T06:57:11Z","timestamp":1521529031000},"page":"891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization"],"prefix":"10.3390","volume":"19","author":[{"given":"Norimichi","family":"Shirafuji","sequence":"first","affiliation":[{"name":"Second Department of Internal Medicine, University of Fukui School of Medicine, Eiheiji-cho, Fukui 910-1193, Japan"},{"name":"Department of Aging and Dementia (DAD), University of Fukui School of Medicine, Eiheiji-cho, 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, University of Fukui School of Medicine, Eiheiji-cho, Fukui 910-1193, Japan"},{"name":"Department of Aging and Dementia (DAD), University of Fukui School of Medicine, Eiheiji-cho, Fukui 910-1193, Japan"},{"name":"Life Science Innovation Center, University of Fukui School of Medicine, Eiheiji-cho, 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 3224, USA"}],"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 Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Yoshida","sequence":"additional","affiliation":[{"name":"National Center for Geriatrics and Gerontology (NCGG), Aichi 474-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouji","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, University of Fukui School of Medicine, Eiheiji-cho, 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, University of Fukui School of Medicine, Eiheiji-cho, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Yamamura","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, University of Fukui School of Medicine, Eiheiji-cho, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Kuriyama","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Attack Ota Memorial Hospital, Hiroshima 720-0825, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunari","family":"Nakamoto","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, University of Fukui School of Medicine, Eiheiji-cho, Fukui 910-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1146\/annurev.neuro.24.1.1121","article-title":"Neurodegenerative tauopathies","volume":"24","author":"Lee","year":"2001","journal-title":"Annu. 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