title: Tau monoclonal antibody generation based on humanized yeast models: impact on Tau oligomerization and diagnostics.
abstract: A link between Tau phosphorylation and aggregation has been shown in different models for Alzheimer disease, including yeast. We used human Tau purified from yeast models to generate new monoclonal antibodies, of which three were further characterized. The first antibody, ADx201, binds the Tau proline-rich region independently of the phosphorylation status, whereas the second, ADx215, detects an epitope formed by the Tau N terminus when Tau is not phosphorylated at Tyr(18). For the third antibody, ADx210, the binding site could not be determined because its epitope is probably conformational. All three antibodies stained tangle-like structures in different brain sections of THY-Tau22 transgenic mice and Alzheimer patients, and ADx201 and ADx210 also detected neuritic plaques in the cortex of the patient brains. In hippocampal homogenates from THY-Tau22 mice and cortex homogenates obtained from Alzheimer patients, ADx215 consistently stained specific low order Tau oligomers in diseased brain, which in size correspond to Tau dimers. ADx201 and ADx210 additionally reacted to higher order Tau oligomers and presumed prefibrillar structures in the patient samples. Our data further suggest that formation of the low order Tau oligomers marks an early disease stage that is initiated by Tau phosphorylation at N-terminal sites. Formation of higher order oligomers appears to require additional phosphorylation in the C terminus of Tau. When used to assess Tau levels in human cerebrospinal fluid, the antibodies permitted us to discriminate patients with Alzheimer disease or other dementia like vascular dementia, indicative that these antibodies hold promising diagnostic potential.
authors.affiliation: From Functional Biology, KU Leuven, Kasteelpark Arenberg 31 Box 2433, 3001 Heverlee, Belgium.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rosseels
authors.affiliation: From Functional Biology, KU Leuven, Kasteelpark Arenberg 31 Box 2433, 3001 Heverlee, Belgium, ADx NeuroSciences NV, Technologiepark Zwijnaarde 4, 9052 Ghent, Belgium, Fujirebio Europe, Technologiepark Zwijnaarde 6, 9052 Ghent, Belgium.
authors.forename: Jeff
authors.initials: J
authors.lastname: Van den Brande
authors.affiliation: INSERM, UMR1172, JPArc, Alzheimer & Tauopathies, Rue Polonovski, 59045 Lille, France, the Faculté de Médecine, Université de Lille, Place de Verdun, 59045 Lille, France, the Memory Clinic, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Violet
authors.affiliation: ADx NeuroSciences NV, Technologiepark Zwijnaarde 4, 9052 Ghent, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jacobs
authors.affiliation: Fujirebio Europe, Technologiepark Zwijnaarde 6, 9052 Ghent, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Grognet
authors.affiliation: Université Lille Nord de France, 59000 Lille, France, CNRS, UMR8576 Structural and Functional Glycobiology, 59650 Villeneuve d'Ascq, France.
authors.forename: Juan
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Université Lille Nord de France, 59000 Lille, France, CNRS, UMR8576 Structural and Functional Glycobiology, 59650 Villeneuve d'Ascq, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Huvent
authors.affiliation: From Functional Biology, KU Leuven, Kasteelpark Arenberg 31 Box 2433, 3001 Heverlee, Belgium.
authors.forename: Marina
authors.initials: M
authors.lastname: Caldara
authors.affiliation: From Functional Biology, KU Leuven, Kasteelpark Arenberg 31 Box 2433, 3001 Heverlee, Belgium.
authors.forename: Erwin
authors.initials: E
authors.lastname: Swinnen
authors.affiliation: INSERM, UMR1172, JPArc, Alzheimer & Tauopathies, Rue Polonovski, 59045 Lille, France, the Faculté de Médecine, Université de Lille, Place de Verdun, 59045 Lille, France, the Memory Clinic, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Papegaey
authors.affiliation: INSERM, UMR1172, JPArc, Alzheimer & Tauopathies, Rue Polonovski, 59045 Lille, France, the Faculté de Médecine, Université de Lille, Place de Verdun, 59045 Lille, France, the Memory Clinic, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Caillierez
authors.affiliation: INSERM, UMR1172, JPArc, Alzheimer & Tauopathies, Rue Polonovski, 59045 Lille, France, the Faculté de Médecine, Université de Lille, Place de Verdun, 59045 Lille, France, the Memory Clinic, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Buée-Scherrer
authors.affiliation: the Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, 2610 Wilrijk, Belgium, and the Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, 2660 Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Université Lille Nord de France, 59000 Lille, France, CNRS, UMR8576 Structural and Functional Glycobiology, 59650 Villeneuve d'Ascq, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.affiliation: INSERM, UMR1172, JPArc, Alzheimer & Tauopathies, Rue Polonovski, 59045 Lille, France, the Faculté de Médecine, Université de Lille, Place de Verdun, 59045 Lille, France, the Memory Clinic, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Morvane
authors.initials: M
authors.lastname: Colin
authors.affiliation: INSERM, UMR1172, JPArc, Alzheimer & Tauopathies, Rue Polonovski, 59045 Lille, France, the Faculté de Médecine, Université de Lille, Place de Verdun, 59045 Lille, France, the Memory Clinic, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: INSERM, UMR1172, JPArc, Alzheimer & Tauopathies, Rue Polonovski, 59045 Lille, France, the Faculté de Médecine, Université de Lille, Place de Verdun, 59045 Lille, France, the Memory Clinic, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Galas
authors.affiliation: ADx NeuroSciences NV, Technologiepark Zwijnaarde 4, 9052 Ghent, Belgium, Eugeen.vanmechelen@adxneurosciences.com.
authors.forename: Eugeen
authors.initials: E
authors.lastname: Vanmechelen
authors.affiliation: From Functional Biology, KU Leuven, Kasteelpark Arenberg 31 Box 2433, 3001 Heverlee, Belgium, joris.winderickx@bio.kuleuven.be.
authors.forename: Joris
authors.initials: J
authors.lastname: Winderickx
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal; D019921:Biotinylation; D015153:Blotting, Western; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007114:Immunization; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009682:Magnetic Resonance Spectroscopy; D021962:Membrane Microdomains; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid; D012441:Saccharomyces cerevisiae; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000737:chemistry* / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D016875:tau Proteins
keywords: Alzheimer Disease; Antibody; Protein Folding; Protein Oligomer; Tau Protein (Tau); Yeast