title: Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice.
abstract: Hyperphosphorylation and fibrillar aggregation of the microtubule-associated protein tau are key features of Alzheimer's disease and other tauopathies. To investigate the involvement of tau phosphorylation in the pathological process, we generated a pair of complementary phosphomutant tau knockin mouse lines. One exclusively expresses phosphomimetic tau with 18 glutamate substitutions at serine and/or threonine residues in the proline-rich and first microtubule-binding domains to model hyperphosphorylation, whereas its phosphodefective counterpart has matched alanine substitutions. Consistent with expected effects of genuine phosphorylation, association of the phosphomimetic tau with microtubules and neuronal membranes is severely disrupted in vivo, whereas the phosphodefective mutations have more limited or no effect. Surprisingly, however, age-related mislocalization of tau is evident in both lines, although redistribution appears more widespread and more pronounced in the phosphomimetic tau knockin. Despite these changes, we found no biochemical or immunohistological evidence of pathological tau aggregation in mice of either line up to at least 2 years of age. These findings raise important questions about the role of tau phosphorylation in driving pathology in human tauopathies.
authors.affiliation: Signalling Programme, The Babraham Institute, Cambridge, UK. Electronic address: jon.gilley@babraham.ac.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.affiliation: Laboratory of Histology, Neuroanatomy and Neuropathology, Faculty of Medicine, ULB Neuroscience Institute, Université Libre de Bruxelles, Brussells, Belgium.
authors.forename: Kunie
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Basic and Clinical Neuroscience (PO37), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Anjan
authors.initials: A
authors.lastname: Seereeram
authors.affiliation: Department of Basic and Clinical Neuroscience (PO37), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rodríguez-Martín
authors.affiliation: Department of Basic and Clinical Neuroscience (PO37), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Pooler
authors.affiliation: Signalling Programme, The Babraham Institute, Cambridge, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Sturdee
authors.affiliation: Department of Basic and Clinical Neuroscience (PO37), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Anderton
authors.affiliation: Laboratory of Histology, Neuroanatomy and Neuropathology, Faculty of Medicine, ULB Neuroscience Institute, Université Libre de Bruxelles, Brussells, Belgium.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Brion
authors.affiliation: Department of Basic and Clinical Neuroscience (PO37), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.affiliation: Signalling Programme, The Babraham Institute, Cambridge, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
mesh_terms: D000818:Animals; D006801:Humans; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological; D024801:Tauopathies / Q000235:genetics* / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; C558298:Mapt protein, mouse; D016875:tau Proteins
keywords: Hyperphosphorylation; Knockin mouse; Phosphodefective; Phosphomimetic; Tau; Tauopathy