Prévention des mécanismes de nucléation et propagation de tau par immunothérapie anti-tau ciblant un épitope central
| Autor: | Raphaëlle Caillierez, Mathieu Schmitt, Clément Danis, Martin Citron, Sébastien Carrier, Marie Albert, Luc Buée, Anne Michel, Isabelle Landrieu, Patrick Downey, Georges Mairet-Coello, Sarah Lieger, Emilie Skrobala, Morvane Colin, Jean-Philippe Courade |
|---|---|
| Přispěvatelé: | BUEE, Luc, Appel à projets générique - Transfert différentiel intercellulaire des assemblages de Tau - - SPREADTAU2014 - ANR-14-CE13-0031 - Appel à projets générique - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Caractérisation moléculaire et cellulaire de nanobodies dirigés contre Tau - - ToNIC2018 - ANR-18-CE44-0016 - AAPG2018 - VALID, Alzheimer & Tauopathies [JPArc], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, UCB BioPharma [Braine l’Alleud, Belgium], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Mémoire de Ressources et de Recherche -CMRR [Lille-Bailleul], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro, Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), This work was supported by grants from UCB Biopharma SPRL, the program Investissement d’avenir LabEx (laboratory excellence) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), SPREADTAU ANR-14-CE13–0031, TONIC ANR-18-CE44–0016 and SUSTAIN TUNABLE (I-SITE ULNE). Our laboratories are also supported by LiCEND (Lille Centre of Excellence in Neurodegenerative Disorders), CNRS, Inserm, Me´tropole Europe´enne de Lille, Univ. Lille and DN2M., ANR-14-CE13-0031,SPREADTAU,Transfert différentiel intercellulaire des assemblages de Tau(2014), ANR-18-CE44-0016,ToNIC,Caractérisation moléculaire et cellulaire de nanobodies dirigés contre Tau(2018), CHU Lille, CNRS, Inserm, Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Lille Neurosciences & Cognition (LilNCog) - U 1172 |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Genetically modified mouse medicine.medical_treatment Tau protein Cell Mice Transgenic tau Proteins Antibodies Epitope Epitopes 03 medical and health sciences 0302 clinical medicine Alzheimer Disease In vivo mental disorders propagation medicine Animals Immunologic Factors [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] biology Propagation Seeding Alzheimer\u2019s disease Immunotherapy Brain Neurofibrillary Tangles Original Articles [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy In vitro 3. Good health Disease Models Animal 030104 developmental biology medicine.anatomical_structure Tauopathies Disease Progression biology.protein Cancer research Female [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Neurology (clinical) immunotherapy Antibody [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy Alzheimer’s disease 030217 neurology & neurosurgery seeding |
| Zdroj: | Brain-A Journal of Neurology Brain-A Journal of Neurology, 2019, 142 (6), pp.1736-1750. ⟨10.1093/brain/awz100⟩ Brain |
| ISSN: | 0006-8950 1460-2156 |
| DOI: | 10.1093/brain/awz100⟩ |
| Popis: | Immunotargeting of extracellular tau could slow the prion-like spreading of neurodegeneration. Albert et al. report that antibodies that recognize a central epitope on tau are the most effective at blocking both seeding and propagation of tau pathological species in transgenic mouse models seeded by materials derived from Alzheimer’s disease brains. Tauopathies are neurodegenerative diseases characterized by the intraneuronal accumulation of aggregated tau. The staging of this neurodegenerative process is well established for Alzheimer’s disease as well as for other tauopathies. The stereotypical pattern of tau pathology in these diseases is consistent with the hypothesis that the tau protein can spread in a ‘prion-like’ manner. It proposes that extracellular pathological tau species can transmit pathology from cell to cell. Accordingly, by targeting these spreading species with therapeutic antibodies one should be able to slow or halt the progression of tau pathology. To be effective, antibodies should neutralize the pathological species present in Alzheimer’s disease brains and block their cell-to-cell spread. To evaluate both aspects, tau antibody D, which recognizes an epitope in the central region of tau, and was selected for its outstanding ability to block tau seeding in cell based assays, was used in this study. Here, we addressed two fundamental questions: (i) can this anti-tau antibody neutralize the pathological species present in Alzheimer’s disease brains; and (ii) can it block the cell-to-cell spread of tau seeds in vivo? First, antibody D effectively prevented the induction of tau pathology in the brains of transgenic mice that had been injected with human Alzheimer’s disease brain extracts, showing that it could effectively neutralize the pathological species present in these extracts. Second, by using K18 P301L tau fibrils to induce pathology, we further demonstrated that antibody D was also capable of blocking the progression of tau pathology to distal brain regions. In contrast, an amino-terminal tau antibody, which was less effective at blocking tau seeding in vitro showed less efficacy in reducing Alzheimer’s disease patient tau driven pathology in the transgenic mouse model. We did not address whether the same is true for a spectrum of other amino-terminal antibodies that were tested in vitro. These data highlight important differences between tau antibodies and, when taken together with other recently published data, suggest that epitope may be important for function. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|