title: Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice.
abstract: Neurofibrillary tangles composed of hyperphosphorylated fibrillized tau are found in numerous tauopathies including Alzheimer's disease. Increasing evidence suggests that tau pathology can be transmitted from cell-to-cell; however the mechanisms involved in the initiation of tau fibrillization and spreading of disease linked to progression of tau pathology are poorly understood. We show here that intracerebral injections of preformed synthetic tau fibrils into the hippocampus or frontal cortex of young tau transgenic mice expressing mutant human P301L tau induces tau hyperphosphorylation and aggregation around the site of injection, as well as a time-dependent propagation of tau pathology to interconnected brain areas distant from the injection site. Furthermore, we show that the tau pathology as a consequence of injection of tau preformed fibrils into the hippocampus induces selective loss of CA1 neurons. Together, our data confirm previous studies on the seeded induction and the spreading of tau pathology in a different tau transgenic mouse model and reveals neuronal loss associated with seeded tau pathology in tau transgenic mouse brain. These results further validate the utility of the tau seeding model in studying disease transmission, and provide a more complete in vivo tauopathy model with associated neurodegeneration which can be used to investigate the mechanisms involved in tau aggregation and spreading, as well as aid in the search for disease modifying treatments for Alzheimer's disease and related tauopathies.
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: Eve
authors.initials: E
authors.lastname: Peeraer
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: Astrid
authors.initials: A
authors.lastname: Bottelbergs
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Kolen
authors.affiliation: UCLouvain, Institute of Neuroscience, Group of Cellular and Molecular Neuroscience, B-1200 Woluwe-Saint-Lambert, Belgium.
authors.forename: Ilie-Cosmin
authors.initials: IC
authors.lastname: Stancu
authors.affiliation: UCLouvain, Institute of Neuroscience, Group of Cellular and Molecular Neuroscience, B-1200 Woluwe-Saint-Lambert, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vasconcelos
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Mahieu
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Duytschaever
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Ver Donck
authors.affiliation: Histogenex, B-2020 Antwerp, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Torremans
authors.affiliation: Histogenex, B-2020 Antwerp, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sluydts
authors.affiliation: Histogenex, B-2020 Antwerp, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van Acker
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: John A
authors.initials: JA
authors.lastname: Kemp
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: UCLouvain, Institute of Neuroscience, Group of Cellular and Molecular Neuroscience, B-1200 Woluwe-Saint-Lambert, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium. Electronic address: dmoechar@its.jnj.com.
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000378:metabolism; D024801:Tauopathies / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D016875:tau Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics*
chemical_list: D016875:tau Proteins
keywords: Cell death; Seeding; Spreading; Tau pathology