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The Journal of Neuroscience, January 16, 2008, 28(3):737-748; doi:10.1523/JNEUROSCI.2824-07.2008

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Neurobiology of Disease
The Potential for β-Structure in the Repeat Domain of Tau Protein Determines Aggregation, Synaptic Decay, Neuronal Loss, and Coassembly with Endogenous Tau in Inducible Mouse Models of Tauopathy

Maria-Magdalena Mocanu,^1 * Astrid Nissen,^1 * Katrin Eckermann,¹ Inna Khlistunova,¹ Jacek Biernat,¹ Dagmar Drexler,¹ Olga Petrova,¹ Kai Schönig,³ Hermann Bujard,³ Eckhard Mandelkow,¹ Lepu Zhou,² Gabriele Rune,² and Eva-Maria Mandelkow¹

¹Max Planck Unit for Structural Molecular Biology, 22607 Hamburg, Germany, ²Department of Neuroanatomy, University of Hamburg Medical School, 20146 Hamburg, Germany, and ³Center for Molecular Biology, University of Heidelberg, 69120 Heidelberg, Germany

Correspondence should be addressed to Eva-Maria Mandelkow, Max Planck Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany. Email: mandelkow{at}mpasmb.desy.de

We describe two new transgenic mouse lines for studying pathological changes of Tau protein related to Alzheimer's disease. They are based on the regulatable expression of the four-repeat domain of human Tau carrying the FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation K280 (Tau_RD/K280), or the K280 plus two proline mutations in the hexapeptide motifs (Tau_RD/K280/I277P/I308P). The K280 mutation accelerates aggregation ("proaggregation mutant"), whereas the proline mutations inhibit Tau aggregation in vitro and in cell models ("antiaggregation mutant"). The inducible transgene expression was driven by the forebrain-specific CaMKII (calcium/calmodulin-dependent protein kinase II) promoter. The proaggregation mutant leads to Tau aggregates and tangles as early as 2–3 months after gene expression, even at low expression (70% of endogenous mouse Tau). The antiaggregation mutant does not aggregate even after 22 months of gene expression. Both mutants show missorting of Tau in the somatodendritic compartment and hyperphosphorylation in the repeat domain [KXGS motifs, targets of the kinase MARK (microtubule affinity regulating kinase)]. This indicates that these changes are related to Tau expression rather than aggregation. The proaggregation mutant causes astrogliosis, loss of synapses and neurons from 5 months of gene expression onward, arguing that Tau toxicity is related to aggregation. Remarkably, the human proaggregation mutant Tau_RD coaggregates with mouse Tau, coupled with missorting and hyperphosphorylation at multiple sites. When expression of proaggregation Tau_RD is switched off, soluble and aggregated exogenous Tau_RD disappears within 1.5 months. However, tangles of mouse Tau, hyperphosphorylation, and missorting remain, suggesting an extended lifetime of aggregated wild-type Tau once a pathological conformation and aggregation is induced by a proaggregation Tau species.

Key words: Alzheimer's disease; Tau; aggregation; reversibility; transgenic mouse models; tauopathy

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Received June 21, 2007; revised Nov. 19, 2007; accepted Nov. 23, 2007.

Correspondence should be addressed to Eva-Maria Mandelkow, Max Planck Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany. Email: mandelkow{at}mpasmb.desy.de

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