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Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization

Increased plasma homocysteinemia is considered a risk factor of dementia, including Alzheimer’s disease (AD) and vascular dementia. However, the reason elevated plasma homocysteinemia increases the risk of dementia remains unknown. A pathological hallmark of AD is neurofibrillary tangles (NFTs) that...

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Autores principales: Shirafuji, Norimichi, Hamano, Tadanori, Yen, Shu-Hui, Kanaan, Nicholas M., Yoshida, Hirotaka, Hayashi, Kouji, Ikawa, Masamichi, Yamamura, Osamu, Kuriyama, Masaru, Nakamoto, Yasunari
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877752/
https://www.ncbi.nlm.nih.gov/pubmed/29562600
http://dx.doi.org/10.3390/ijms19030891
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author Shirafuji, Norimichi
Hamano, Tadanori
Yen, Shu-Hui
Kanaan, Nicholas M.
Yoshida, Hirotaka
Hayashi, Kouji
Ikawa, Masamichi
Yamamura, Osamu
Kuriyama, Masaru
Nakamoto, Yasunari
author_facet Shirafuji, Norimichi
Hamano, Tadanori
Yen, Shu-Hui
Kanaan, Nicholas M.
Yoshida, Hirotaka
Hayashi, Kouji
Ikawa, Masamichi
Yamamura, Osamu
Kuriyama, Masaru
Nakamoto, Yasunari
author_sort Shirafuji, Norimichi
collection PubMed
description Increased plasma homocysteinemia is considered a risk factor of dementia, including Alzheimer’s disease (AD) and vascular dementia. 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 (10–1000 µM) 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.
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spelling pubmed-58777522018-04-09 Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization Shirafuji, Norimichi Hamano, Tadanori Yen, Shu-Hui Kanaan, Nicholas M. Yoshida, Hirotaka Hayashi, Kouji Ikawa, Masamichi Yamamura, Osamu Kuriyama, Masaru Nakamoto, Yasunari Int J Mol Sci Article Increased plasma homocysteinemia is considered a risk factor of dementia, including Alzheimer’s disease (AD) and vascular dementia. 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 (10–1000 µM) 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. MDPI 2018-03-17 /pmc/articles/PMC5877752/ /pubmed/29562600 http://dx.doi.org/10.3390/ijms19030891 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shirafuji, Norimichi
Hamano, Tadanori
Yen, Shu-Hui
Kanaan, Nicholas M.
Yoshida, Hirotaka
Hayashi, Kouji
Ikawa, Masamichi
Yamamura, Osamu
Kuriyama, Masaru
Nakamoto, Yasunari
Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization
title Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization
title_full Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization
title_fullStr Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization
title_full_unstemmed Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization
title_short Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization
title_sort homocysteine increases tau phosphorylation, truncation and oligomerization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877752/
https://www.ncbi.nlm.nih.gov/pubmed/29562600
http://dx.doi.org/10.3390/ijms19030891
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