A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau Isoforms
As human Tau undergoes pathologically relevant post-translational modifications when expressed in yeast, the use of humanized yeast models for the generation of novel Tau monoclonal antibodies has previously been proven to be successful. In this study, human Tau2N4R-ΔK280 purified from yeast was use...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-03-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmolb.2020.00048/full |
| _version_ | 1818141900442435584 |
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| author | Joke Verelst Nick Geukens Sabiha Eddarkaoui Dorien Vliegen Elien De Smidt Joëlle Rosseels Vanessa Franssens Sofie Molenberghs Cindy Francois Erik Stoops Maria Bjerke Maria Bjerke Sebastiaan Engelborghs Sebastiaan Engelborghs Mohamed Laghmouchi Sofie Carmans Luc Buée Eugeen Vanmechelen Joris Winderickx Debby Thomas |
| author_facet | Joke Verelst Nick Geukens Sabiha Eddarkaoui Dorien Vliegen Elien De Smidt Joëlle Rosseels Vanessa Franssens Sofie Molenberghs Cindy Francois Erik Stoops Maria Bjerke Maria Bjerke Sebastiaan Engelborghs Sebastiaan Engelborghs Mohamed Laghmouchi Sofie Carmans Luc Buée Eugeen Vanmechelen Joris Winderickx Debby Thomas |
| author_sort | Joke Verelst |
| collection | DOAJ |
| description | As human Tau undergoes pathologically relevant post-translational modifications when expressed in yeast, the use of humanized yeast models for the generation of novel Tau monoclonal antibodies has previously been proven to be successful. In this study, human Tau2N4R-ΔK280 purified from yeast was used for the immunization of mice and subsequent selection of high affinity Tau-specific monoclonal antibodies. The characterization of four novel antibodies in different Tau model systems yielded a phosphorylation-dependent antibody (15A10), an antibody directed to the first microtubule-binding repeat domain (16B12), a carboxy-terminal antibody (20G10) and an antibody targeting an epitope on the hinge of the first and second amino-terminal insert (18F12). The latter was found to be conformation-dependent, suggesting structural differences between the Tau splicing isoforms and allowing insight in the roles played by the amino-terminal inserts. As this monoclonal antibody also has the capacity to detect tangle-like structures in different transgenic Tau mice and neurofibrillary tangles in brain sections of patients diagnosed with Alzheimer's disease, we also tested the diagnostic potential of 18F12 in a pilot study and found this monoclonal antibody to have the ability to discriminate Alzheimer's disease patients from control individuals based on increased Tau levels in the cerebrospinal fluid. |
| first_indexed | 2024-12-11T11:07:14Z |
| format | Article |
| id | doaj.art-db17ced278244261bbf0ac1d62a52471 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-11T11:07:14Z |
| publishDate | 2020-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-db17ced278244261bbf0ac1d62a524712022-12-22T01:09:39ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2020-03-01710.3389/fmolb.2020.00048499624A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau IsoformsJoke Verelst0Nick Geukens1Sabiha Eddarkaoui2Dorien Vliegen3Elien De Smidt4Joëlle Rosseels5Vanessa Franssens6Sofie Molenberghs7Cindy Francois8Erik Stoops9Maria Bjerke10Maria Bjerke11Sebastiaan Engelborghs12Sebastiaan Engelborghs13Mohamed Laghmouchi14Sofie Carmans15Luc Buée16Eugeen Vanmechelen17Joris Winderickx18Debby Thomas19Functional Biology, KU Leuven, Heverlee, BelgiumPharmAbs, KU Leuven, Leuven, BelgiumUniv. Lille, Inserm, CHU-Lille, UMRS1172, Lille Neuroscience & Cognition, LabEx DISTALZ, Alzheimer & Tauopathies, Lille, FranceFunctional Biology, KU Leuven, Heverlee, BelgiumPharmAbs, KU Leuven, Leuven, BelgiumFunctional Biology, KU Leuven, Heverlee, BelgiumFunctional Biology, KU Leuven, Heverlee, BelgiumFunctional Biology, KU Leuven, Heverlee, BelgiumADx NeuroSciences NV, Ghent, BelgiumADx NeuroSciences NV, Ghent, BelgiumReference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Wilrijk, BelgiumDepartment of Neurology and Center for Neurosciences, UZ Brussel and Vrije Universtieit Brussel (VUB), Brussels, BelgiumReference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Wilrijk, BelgiumDepartment of Neurology and Center for Neurosciences, UZ Brussel and Vrije Universtieit Brussel (VUB), Brussels, BelgiumreMYND NV, Bio-Incubator, Heverlee, BelgiumreMYND NV, Bio-Incubator, Heverlee, BelgiumUniv. Lille, Inserm, CHU-Lille, UMRS1172, Lille Neuroscience & Cognition, LabEx DISTALZ, Alzheimer & Tauopathies, Lille, FranceADx NeuroSciences NV, Ghent, BelgiumFunctional Biology, KU Leuven, Heverlee, BelgiumPharmAbs, KU Leuven, Leuven, BelgiumAs human Tau undergoes pathologically relevant post-translational modifications when expressed in yeast, the use of humanized yeast models for the generation of novel Tau monoclonal antibodies has previously been proven to be successful. In this study, human Tau2N4R-ΔK280 purified from yeast was used for the immunization of mice and subsequent selection of high affinity Tau-specific monoclonal antibodies. The characterization of four novel antibodies in different Tau model systems yielded a phosphorylation-dependent antibody (15A10), an antibody directed to the first microtubule-binding repeat domain (16B12), a carboxy-terminal antibody (20G10) and an antibody targeting an epitope on the hinge of the first and second amino-terminal insert (18F12). The latter was found to be conformation-dependent, suggesting structural differences between the Tau splicing isoforms and allowing insight in the roles played by the amino-terminal inserts. As this monoclonal antibody also has the capacity to detect tangle-like structures in different transgenic Tau mice and neurofibrillary tangles in brain sections of patients diagnosed with Alzheimer's disease, we also tested the diagnostic potential of 18F12 in a pilot study and found this monoclonal antibody to have the ability to discriminate Alzheimer's disease patients from control individuals based on increased Tau levels in the cerebrospinal fluid.https://www.frontiersin.org/article/10.3389/fmolb.2020.00048/fullyeastSaccharomyces cerevisiaeTauTau isoformsmonoclonal antibodiesconformational differences |
| spellingShingle | Joke Verelst Nick Geukens Sabiha Eddarkaoui Dorien Vliegen Elien De Smidt Joëlle Rosseels Vanessa Franssens Sofie Molenberghs Cindy Francois Erik Stoops Maria Bjerke Maria Bjerke Sebastiaan Engelborghs Sebastiaan Engelborghs Mohamed Laghmouchi Sofie Carmans Luc Buée Eugeen Vanmechelen Joris Winderickx Debby Thomas A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau Isoforms Frontiers in Molecular Biosciences yeast Saccharomyces cerevisiae Tau Tau isoforms monoclonal antibodies conformational differences |
| title | A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau Isoforms |
| title_full | A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau Isoforms |
| title_fullStr | A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau Isoforms |
| title_full_unstemmed | A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau Isoforms |
| title_short | A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau Isoforms |
| title_sort | novel tau antibody detecting the first amino terminal insert reveals conformational differences among tau isoforms |
| topic | yeast Saccharomyces cerevisiae Tau Tau isoforms monoclonal antibodies conformational differences |
| url | https://www.frontiersin.org/article/10.3389/fmolb.2020.00048/full |
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