Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization.
Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2020-01-01
|
Series: | PLoS ONE |
Online Access: | https://doi.org/10.1371/journal.pone.0224952 |
id |
doaj-34baaf1a972c4935803fbc027e1a54e2 |
---|---|
record_format |
Article |
spelling |
doaj-34baaf1a972c4935803fbc027e1a54e22021-03-04T12:55:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01157e022495210.1371/journal.pone.0224952Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization.Hamad YadikarIsabel TorresGabrielle AielloMilin KurupZhihui YangFan LinFiras KobeissyRichard YostKevin K WangTauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and form neurofibrillary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed contrasting results between the two neuronal cultures. This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative diseases.https://doi.org/10.1371/journal.pone.0224952 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hamad Yadikar Isabel Torres Gabrielle Aiello Milin Kurup Zhihui Yang Fan Lin Firas Kobeissy Richard Yost Kevin K Wang |
spellingShingle |
Hamad Yadikar Isabel Torres Gabrielle Aiello Milin Kurup Zhihui Yang Fan Lin Firas Kobeissy Richard Yost Kevin K Wang Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. PLoS ONE |
author_facet |
Hamad Yadikar Isabel Torres Gabrielle Aiello Milin Kurup Zhihui Yang Fan Lin Firas Kobeissy Richard Yost Kevin K Wang |
author_sort |
Hamad Yadikar |
title |
Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. |
title_short |
Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. |
title_full |
Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. |
title_fullStr |
Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. |
title_full_unstemmed |
Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. |
title_sort |
screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2020-01-01 |
description |
Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and form neurofibrillary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed contrasting results between the two neuronal cultures. This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative diseases. |
url |
https://doi.org/10.1371/journal.pone.0224952 |
work_keys_str_mv |
AT hamadyadikar screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization AT isabeltorres screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization AT gabrielleaiello screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization AT milinkurup screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization AT zhihuiyang screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization AT fanlin screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization AT firaskobeissy screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization AT richardyost screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization AT kevinkwang screeningoftauproteinkinaseinhibitorsinatauopathyrelevantcellbasedmodeloftauhyperphosphorylationandoligomerization |
_version_ |
1714801057492631552 |