title: Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy.
abstract: Accumulation of hyperphosphorylated tau directly correlates with cognitive decline in Alzheimer's disease and other primary tauopathies. One therapeutic strategy may be to reduce total tau expression. We identified antisense oligonucleotides (ASOs) that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and preexisting phosphorylated tau and Thioflavin S pathology were reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In addition, mouse survival was extended, and pathological tau seeding was reversed. In nonhuman primates, tau ASOs distributed throughout the brain and spinal cord and reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid. These data support investigation of a tau-lowering therapy in human patients who have tau-positive inclusions even after pathological tau deposition has begun.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: DeVos
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Miller
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Schoch
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Brandon B
authors.initials: BB
authors.lastname: Holmes
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Carey S
authors.initials: CS
authors.lastname: Kebodeaux
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wegener
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 90201, USA.
authors.forename: Hien
authors.initials: H
authors.lastname: Tran
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 90201, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Nichols
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 90201, USA.
authors.forename: Tom A
authors.initials: TA
authors.lastname: Zanardi
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 90201, USA.
authors.forename: Holly B
authors.initials: HB
authors.lastname: Kordasiewicz
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 90201, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 90201, USA.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Marc I
authors.initials: MI
authors.lastname: Diamond
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA. miller.t@wustl.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology; D002470:Cell Survival; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010766:Phosphorylation; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism*
chemical_list: D016376:Oligonucleotides, Antisense; D016875:tau Proteins