Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein |
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Authors: | A Probst J Götz K H Wiederhold M Tolnay C Mistl AL Jaton M Hong T Ishihara V M-Y Lee J Q Trojanowski R Jakes R A Crowther M G Spillantini K Bürki M Goedert |
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Institution: | Abteilung Neuropathologie, Institut für Pathologie, Universit?t Basel, CH-4003 Basel, Switzerland, CH Abteilung für psychiatrische Forschung, Universit?t Zürich, CH-8008, Zürich Switzerland, CH Novartis Pharma, Inc., S-386.227 and S-386.809, CH-4002 Basel, Switzerland, CH Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-4283, USA, US MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK e-mail: mg@mrc-lmb.cam.ac.uk, Tel.: +44-1223-402036, Fax: +44-1223-402197, GB Department of Neurology, Adrian Building, University of Cambridge, Cambridge CB2 2PY, UK, GB Institut für Labortierkunde, Universit?t Zürich-Irchel, CH-8057 Zürich, Switzerland, CH
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Abstract: | Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome
17. Some of these mutations lead to an overproduction of tau isoforms with four microtubule-binding repeats. Here we have
expressed the longest four-repeat human brain tau isoform in transgenic mice under the control of the murine Thy1 promoter.
Transgenic mice aged 3 weeks to 25 months overexpressed human tau protein in nerve cells of brain and spinal cord. Numerous
abnormal, tau-immunoreactive nerve cell bodies and dendrites were seen. In addition, large numbers of pathologically enlarged
axons containing neurofilament- and tau-immunoreactive spheroids were present, especially in spinal cord. Signs of Wallerian
degeneration and neurogenic muscle atrophy were observed. When motor function was tested, transgenic mice showed signs of
muscle weakness. Taken together, these findings demonstrate that overexpression of human four-repeat tau leads to a central
and peripheral axonopathy that results in nerve cell dysfunction and amyotrophy.
Received: 28 September 1999 / Revised, accepted: 18 November 1999 |
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Keywords: | Amyotrophy Axonopathy Neurofilaments Tau protein Transgenic mice |
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