title: Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy.
abstract: The microtubule-associated protein tau is implicated in various neurodegenerative diseases including Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, which are characterized by intracellular accumulation of hyperphosphorylated tau. Mutations in the tau gene MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In the human central nervous system, six tau isoforms are expressed, and imbalances in tau isoform ratios are associated with pathology. To date, few animal models of tauopathy allow for the potential influence of these protein isoforms, relying instead on cDNA-based transgene expression. Using the P1-derived artificial chromosome (PAC) technology, we created mouse lines expressing all six tau isoforms from the human MAPT locus, harbouring either the wild-type sequence or the disease-associated N296H mutation on an endogenous Mapt-/- background. Animals expressing N296H mutant tau recapitulated early key features of tauopathic disease, including a tau isoform imbalance and tau hyperphosphorylation in the absence of somatodendritic tau inclusions. Furthermore, N296H animals displayed behavioural anomalies such as hyperactivity, increased time in the open arms of the elevated plus maze and increased immobility during the tail suspension test. The mouse models described provide an excellent model to study the function of wild-type or mutant tau in a highly physiological setting.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Heike J
authors.initials: HJ
authors.lastname: Wobst
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Franziska
authors.initials: F
authors.lastname: Denk
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Achilleas
authors.initials: A
authors.lastname: Livieratos
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Tonya N
authors.initials: TN
authors.lastname: Taylor
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Knudsen
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Nora
authors.initials: N
authors.lastname: Bengoa-Vergniory
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Bannerman
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.|Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D004195:Disease Models, Animal; D015870:Gene Expression; D051379:Mice; D050505:Mutant Proteins / Q000032:analysis / Q000235:genetics; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D024801:Tauopathies / Q000473:pathology*; D016875:tau Proteins / Q000032:analysis* / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D050505:Mutant Proteins; D020033:Protein Isoforms; D016875:tau Proteins