title: Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model.
abstract: Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110.
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.
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.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Miller
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Chun
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Michaela
authors.initials: M
authors.lastname: Norrbom
authors.affiliation: Taylor Family Institute for Innovative Psychiatric Research, Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110.
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Hana N
authors.initials: HN
authors.lastname: Dawson
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110. Electronic address: millert@neuro.wustl.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D005091:Exons / Q000235:genetics; D006801:Humans; D057967:Infusions, Intraventricular; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000187:drug effects; D009425:Nesting Behavior / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
chemical_list: C054369:MAPT protein, human; C558298:Mapt protein, mouse; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D016875:tau Proteins