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Transmission and spreading of tauopathy in transgenic mouse brain

Abstract

Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease1. In the disease process, neuronal tau inclusions first appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex2. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular β-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. An abundance of tau inclusions, in the absence of β-amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases1. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia3,4,5. Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein6,8. By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration7,8. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions.

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Figure 1: Induction of filamentous tau pathology in ALZ17 mice injected with brain extract from mice transgenic for human P301S tau.
Figure 2: Temporal increase in the number of Gallyas-Braak-positive structures at the injection sites (–2.
Figure 3: Spreading of filamentous tau pathology in ALZ17 mice injected with brain extract from mice transgenic for human P301S tau.
Figure 4: Induction of filamentous tau pathology in non-transgenic C57BL/6 mice injected with brain extract from mice transgenic for human P301S tau.

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Acknowledgements

This work was supported by the Swiss National Science Foundation (3100AO-120261) (M.T.), the Alzheimer Association (ZEN-06-27341), the German National Genome Network (NGFN-Plus) and the German Competence Network in Degenerative Dementias (01GI0705) (M.J.), the U.K. Medical Research Council (R.A.C, G.F., M.G.) and the U.K. Alzheimer's Research Trust (M.G.). We thank K.H. Wiederhold (Novartis Institutes for Biomedical Research, Basel) and N. Schaeren-Wiemers (University Hospital Basel) for antibodies and helpful discussions.

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F.C., R.A.C., M.G. and M.T. designed the experiments, coordinated the project and wrote the manuscript. M.J. initiated the study. F.C., T.B., R.A.C. D.A., G.F., A.K.S. and M.G. performed the experimental work. A.P. assisted with assessment and interpretation of initiation and neuroanatomical spreading of tau pathology. M.B. performed statistical analyses. M.S., S.F. and M.J. contributed to data and manuscript discussions.

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Correspondence to Michel Goedert or Markus Tolnay.

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Clavaguera, F., Bolmont, T., Crowther, R. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11, 909–913 (2009). https://doi.org/10.1038/ncb1901

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