caa a22 4500 606177469 CHVBK 20210128100752.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00018-014-1804-z doi (NATIONALLICENCE)springer-10.1007/s00018-014-1804-z Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration [Elektronische Daten] [V. Melis, C. Zabke, K. Stamer, M. Magbagbeolu, K. Schwab, P. Marschall, R. Veh, S. Bachmann, S. Deiana, P.-H. Moreau, K. Davidson, K. Harrington, J. Rickard, D. Horsley, R. Garman, M. Mazurkiewicz, G. Niewiadomska, C. Wischik, C. Harrington, G. Riedel, F. Theuring] A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology. The Author(s), 2014 Tau protein nationallicence Transgenic mice nationallicence P301L nationallicence Truncated cDNA Tau296-390 nationallicence Motor impairment nationallicence Spatial cognition nationallicence Melis V. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Zabke C. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut Stamer K. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut Magbagbeolu M. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut Schwab K. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut Marschall P. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut Veh R. Charité-Universitätsmedizin Berlin, Institute of Anatomy, Berlin, Germany aut Bachmann S. Charité-Universitätsmedizin Berlin, Institute of Anatomy, Berlin, Germany aut Deiana S. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Moreau P.-H School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Davidson K. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Harrington K. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Rickard J. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Horsley D. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Garman R. Consultants in Veterinary Pathology Inc., Murrysville, PA, USA aut Mazurkiewicz M. Nencki Institute, Warsaw, Poland aut Niewiadomska G. Nencki Institute, Warsaw, Poland aut Wischik C. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Harrington C. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut Riedel G. School of Medical Sciences, University of Aberdeen, AB25 2ZD, Foresterhill, Scotland, UK aut Theuring F. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut Cellular and Molecular Life Sciences Springer Basel 72/11(2015-06-01), 2199-2222 1420-682X 72:11<2199 2015 72 18 https://doi.org/10.1007/s00018-014-1804-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1804-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Melis V. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Zabke C. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut NATIONALLICENCE 700 1- Stamer K. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut NATIONALLICENCE 700 1- Magbagbeolu M. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut NATIONALLICENCE 700 1- Schwab K. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut NATIONALLICENCE 700 1- Marschall P. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut NATIONALLICENCE 700 1- Veh R. Charité-Universitätsmedizin Berlin, Institute of Anatomy, Berlin, Germany aut NATIONALLICENCE 700 1- Bachmann S. Charité-Universitätsmedizin Berlin, Institute of Anatomy, Berlin, Germany aut NATIONALLICENCE 700 1- Deiana S. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Moreau P.-H School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Davidson K. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Harrington K. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Rickard J. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Horsley D. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Garman R. Consultants in Veterinary Pathology Inc., Murrysville, PA, USA aut NATIONALLICENCE 700 1- Mazurkiewicz M. Nencki Institute, Warsaw, Poland aut NATIONALLICENCE 700 1- Niewiadomska G. Nencki Institute, Warsaw, Poland aut NATIONALLICENCE 700 1- Wischik C. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Harrington C. School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK aut NATIONALLICENCE 700 1- Riedel G. School of Medical Sciences, University of Aberdeen, AB25 2ZD, Foresterhill, Scotland, UK aut NATIONALLICENCE 700 1- Theuring F. CCR/Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Institute of Pharmacology, Hessische Str. 3-4, 10115, Berlin, Germany aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/11(2015-06-01), 2199-2222 1420-682X 72:11<2199 2015 72 18