title: High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration.
abstract: BACKGROUND
  Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer's disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease.
  
  
  RESULTS
  We generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence.
  
  
  CONCLUSIONS
  Features of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes.
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
authors.forename: Jeanna M
authors.initials: JM
authors.lastname: Wheeler
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.|Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McMillan
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Hawk
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Iba
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Robinson
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Dombroski
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Doori
authors.initials: D
authors.lastname: Jeong
authors.affiliation: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Dichter
authors.affiliation: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Halvor
authors.initials: H
authors.lastname: Juul
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Loomis
authors.affiliation: Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Raskind
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland, OH, 44195, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. gerardsc@mail.med.UPENN.edu.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA. kraemerb@uw.edu.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA. kraemerb@uw.edu.|Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA. kraemerb@uw.edu.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Kraemer
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology*; D056915:DNA Copy Number Variations / Q000235:genetics*; D018450:Disease Progression; D004569:Electroencephalography; D005106:Exploratory Behavior / Q000502:physiology; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D053580:Muscle Strength / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D024801:Tauopathies / Q000150:complications* / Q000235:genetics; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins