Syk inhibitors reduce tau protein phosphorylation and oligomerization
Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblast...
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| Language: | English |
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Elsevier
2024-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124002560 |
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| author | Tomohisa Yamaguchi Tadanori Hamano Kiyonao Sada Rei Asano Nicholas M. Kanaan Hirohito Sasaki Shu-Hui Yen Yuki Kitazaki Yoshinori Endo Soichi Enomoto Norimichi Shirafuji Masamichi Ikawa Osamu Yamamura Youshi Fujita Koji Aoki Hironobu Naiki Maho Morishima Yuko Saito Shigeo Murayama Yasunari Nakamoto |
| author_facet | Tomohisa Yamaguchi Tadanori Hamano Kiyonao Sada Rei Asano Nicholas M. Kanaan Hirohito Sasaki Shu-Hui Yen Yuki Kitazaki Yoshinori Endo Soichi Enomoto Norimichi Shirafuji Masamichi Ikawa Osamu Yamamura Youshi Fujita Koji Aoki Hironobu Naiki Maho Morishima Yuko Saito Shigeo Murayama Yasunari Nakamoto |
| author_sort | Tomohisa Yamaguchi |
| collection | DOAJ |
| description | Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors—BAY 61–3606 and R406—on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated in vivo using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3β expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD. |
| format | Article |
| id | doaj-art-239a93f919264675ad69ceb404dfc1d2 |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-239a93f919264675ad69ceb404dfc1d22025-08-20T01:48:03ZengElsevierNeurobiology of Disease1095-953X2024-10-0120110665610.1016/j.nbd.2024.106656Syk inhibitors reduce tau protein phosphorylation and oligomerizationTomohisa Yamaguchi0Tadanori Hamano1Kiyonao Sada2Rei Asano3Nicholas M. Kanaan4Hirohito Sasaki5Shu-Hui Yen6Yuki Kitazaki7Yoshinori Endo8Soichi Enomoto9Norimichi Shirafuji10Masamichi Ikawa11Osamu Yamamura12Youshi Fujita13Koji Aoki14Hironobu Naiki15Maho Morishima16Yuko Saito17Shigeo Murayama18Yasunari Nakamoto19Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanSecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Department of Aging and Dementia (DAD), Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Life Science Innovation Center, University of Fukui, Fukui, Japan; Corresponding author at: Second Department of Internal Medicine, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji, Fukui 910-1193, Japan.Department of Genome Science and Microbiology, Faculty of Medical Sciences, University of Fukui, Fukui, JapanSecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanDepartment of Translational Neuroscience, College of Human Medicine, Michigan State University, MI, USASecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanDepartment of Neuroscience, Mayo Clinic Jacksonville, FL, USASecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanSecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanSecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanSecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanSecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanSecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanDepartment of Neurology, Fujita Neurological Hospital, Fukui, JapanDepartment of Pharmacology, Faculty of Medical Sciences, University of Fukui, Fukui, JapanDepartment of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui, JapanBrain Bank for Aging Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, JapanBrain Bank for Aging Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, JapanBrain Bank for Aging Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, JapanSecond Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, JapanSpleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors—BAY 61–3606 and R406—on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated in vivo using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3β expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD.http://www.sciencedirect.com/science/article/pii/S0969996124002560Alzheimer's diseaseSykTauPhosphorylationAutophagyCaspase 3 |
| spellingShingle | Tomohisa Yamaguchi Tadanori Hamano Kiyonao Sada Rei Asano Nicholas M. Kanaan Hirohito Sasaki Shu-Hui Yen Yuki Kitazaki Yoshinori Endo Soichi Enomoto Norimichi Shirafuji Masamichi Ikawa Osamu Yamamura Youshi Fujita Koji Aoki Hironobu Naiki Maho Morishima Yuko Saito Shigeo Murayama Yasunari Nakamoto Syk inhibitors reduce tau protein phosphorylation and oligomerization Neurobiology of Disease Alzheimer's disease Syk Tau Phosphorylation Autophagy Caspase 3 |
| title | Syk inhibitors reduce tau protein phosphorylation and oligomerization |
| title_full | Syk inhibitors reduce tau protein phosphorylation and oligomerization |
| title_fullStr | Syk inhibitors reduce tau protein phosphorylation and oligomerization |
| title_full_unstemmed | Syk inhibitors reduce tau protein phosphorylation and oligomerization |
| title_short | Syk inhibitors reduce tau protein phosphorylation and oligomerization |
| title_sort | syk inhibitors reduce tau protein phosphorylation and oligomerization |
| topic | Alzheimer's disease Syk Tau Phosphorylation Autophagy Caspase 3 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124002560 |
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