title: Early-onset axonal pathology in a novel P301S-Tau transgenic mouse model of frontotemporal lobar degeneration.
abstract: OBJECTIVE
  Tau becomes hyperphosphorylated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-tau), resulting in functional deficits of neurones, neurofibrillary tangle (NFT) formation and eventually dementia. Expression of mutant human tau in the brains of transgenic mice has produced different lines that recapitulate various aspects of FTLD-tau and AD. In this study, we characterized the novel P301S mutant tau transgenic mouse line, TAU58/2.
  
  
  METHODS
  Both young and aged TAU58/2 mice underwent extensive motor testing, after which brain tissue was analysed with immunohistochemistry, silver staining, electron microscopy and Western blotting. Tissue from various FTLD subtypes and AD patients was also analysed for comparison.
  
  
  RESULTS
  TAU58/2 mice presented with early-onset motor deficits, which became more pronounced with age. Throughout the brains of these mice, tau was progressively hyperphosphorylated resulting in increased NFT formation with age. In addition, frequent axonal swellings that stained intensively for neurofilament (NF) were present in young TAU58/2 mice prior to NFT formation. Similar axonal pathology was also observed in human FTLD-tau and AD. Interestingly, activated microglia were found in close proximity to neurones harbouring transgenic tau, but were not associated with NF-positive axonal swellings.
  
  
  CONCLUSIONS
  In TAU58/2 mice, early tau pathology induces functional deficits of neurones associated with NF pathology. This appears to be specific to tau, as similar changes are observed in FTLD-tau, but not in FTLD with TDP-43 inclusions. Therefore, TAU58/2 mice recapitulate aspects of human FTLD-tau and AD pathology, and will become instrumental in studying disease mechanisms and therapeutics in the future.
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Janet
authors.initials: J
authors.lastname: van Eersel
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Stevens
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Przybyla
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Amadeus
authors.initials: A
authors.lastname: Gladbach
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Kristie
authors.initials: K
authors.lastname: Stefanoska
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chesed Kai-Xin
authors.initials: CK
authors.lastname: Chan
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Ong
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, Australia.|Neuroscience Research Australia, Sydney, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Hodges
authors.affiliation: Discipline of Pathology, University of Sydney, Sydney, Australia.
authors.forename: Greg T
authors.initials: GT
authors.lastname: Sutherland
authors.affiliation: Discipline of Pathology, University of Sydney, Sydney, Australia.
authors.forename: Jillian J
authors.initials: JJ
authors.lastname: Kril
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, Australia.|Neuroscience Research Australia, Sydney, Australia.
authors.forename: Glenda M
authors.identifier: http://orcid.org/0000-0003-0422-8398
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Dementia Research Unit, Department of Anatomy, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.|Neuroscience Research Australia, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016875:tau Proteins
keywords: Alzheimer's disease; Tau; frontotemporal lobar degeneration; mouse model; neurofilament