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 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.
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.|Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kiran
K
Yanamandra
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.|Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Najla
N
Kfoury
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.|Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Hong
H
Jiang
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.|Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Thomas E
TE
Mahan
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.|Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Shengmei
S
Ma
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Susan E
SE
Maloney
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
David F
DF
Wozniak
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.|Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Marc I
MI
Diamond
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.|Charles F and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
David M
DM
Holtzman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D057967:Infusions, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D024801:Tauopathies / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism / Q000633:toxicity
D000911:Antibodies, Monoclonal; D016875:tau Proteins