Anti-Tau Antibodies that Block Tau Aggregate Seeding In Vitro Markedly Decrease Pathology and Improve Cognition In Vivo
Tau aggregation occurs in neurodegenerative diseases including Alzheimer’s disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice...
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| Published in | Neuron (Cambridge, Mass.) Vol. 80; no. 2; pp. 402 - 414 |
|---|---|
| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
16.10.2013
Elsevier Limited |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0896-6273 1097-4199 1097-4199 |
| DOI | 10.1016/j.neuron.2013.07.046 |
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| Abstract | Tau aggregation occurs in neurodegenerative diseases including Alzheimer’s disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.
•Anti-tau antibodies block intracellular tau aggregation induced by tau seeds•Anti-tau antibodies strongly reduce tau pathology in vivo•Anti-tau antibodies decrease tau seeding activity in vivo•Anti-tau antibodies improve cognition
Yanamandra et al. find that antibodies that block aggregated forms of the tau protein from entering cells and seeding further tau aggregation have beneficial effects in an animal model that is relevant for Alzheimer’s disease and related disorders. |
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| AbstractList | Tau aggregation occurs in neurodegenerative diseases including Alzheimer’s disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.
•Anti-tau antibodies block intracellular tau aggregation induced by tau seeds•Anti-tau antibodies strongly reduce tau pathology in vivo•Anti-tau antibodies decrease tau seeding activity in vivo•Anti-tau antibodies improve cognition
Yanamandra et al. find that antibodies that block aggregated forms of the tau protein from entering cells and seeding further tau aggregation have beneficial effects in an animal model that is relevant for Alzheimer’s disease and related disorders. Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies.trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to blocktrans-cellular aggregate propagation will be a productive treatment strategy. Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein, and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused 3 effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy. Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy. Tau aggregation occurs in neurodegenerative diseases including Alzheimers disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy. Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy. |
| Author | Holtzman, David M. Kfoury, Najla Yanamandra, Kiran Mahan, Thomas E. Ma, Shengmei Wozniak, David F. Diamond, Marc I. Jiang, Hong Maloney, Susan E. |
| AuthorAffiliation | 1 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA 3 Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA 2 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA 4 Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA |
| AuthorAffiliation_xml | – name: 1 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA – name: 4 Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA – name: 2 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA – name: 3 Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA |
| Author_xml | – sequence: 1 givenname: Kiran surname: Yanamandra fullname: Yanamandra, Kiran organization: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 2 givenname: Najla surname: Kfoury fullname: Kfoury, Najla organization: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 3 givenname: Hong surname: Jiang fullname: Jiang, Hong organization: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 4 givenname: Thomas E. surname: Mahan fullname: Mahan, Thomas E. organization: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 5 givenname: Shengmei surname: Ma fullname: Ma, Shengmei organization: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 6 givenname: Susan E. surname: Maloney fullname: Maloney, Susan E. organization: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 7 givenname: David F. surname: Wozniak fullname: Wozniak, David F. organization: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 8 givenname: Marc I. surname: Diamond fullname: Diamond, Marc I. email: diamondm@neuro.wustl.edu organization: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 9 givenname: David M. surname: Holtzman fullname: Holtzman, David M. email: holtzman@neuro.wustl.edu organization: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24075978$$D View this record in MEDLINE/PubMed |
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| Snippet | Tau aggregation occurs in neurodegenerative diseases including Alzheimer’s disease and many other disorders collectively termed tauopathies. trans-cellular... Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. trans-cellular... Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies.trans-cellular... Tau aggregation occurs in neurodegenerative diseases including Alzheimers disease and many other disorders collectively termed tauopathies. trans-cellular... Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular... |
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| SubjectTerms | Animals Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - immunology Antibodies, Monoclonal - therapeutic use Brain - drug effects Brain - metabolism Brain - pathology Cells, Cultured Cognition Disorders - complications Cognition Disorders - drug therapy Cognition Disorders - physiopathology Disease Gender Humans Immunization Infusions, Intraventricular Mice Mice, Transgenic Microglia - drug effects Pathology Rodents Software Statistical analysis Studies tau Proteins - antagonists & inhibitors tau Proteins - immunology tau Proteins - metabolism tau Proteins - toxicity Tauopathies - complications Tauopathies - drug therapy Tauopathies - pathology Tauopathies - psychology |
| Title | Anti-Tau Antibodies that Block Tau Aggregate Seeding In Vitro Markedly Decrease Pathology and Improve Cognition In Vivo |
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