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J. Biol. Chem., Vol. 282, Issue 43, 31755-31765, October 26, 2007

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The -Propensity of Tau Determines Aggregation and Synaptic Loss in Inducible Mouse Models of Tauopathy^*

Katrin Eckermann, Maria-Magdalena Mocanu, Inna Khlistunova, Jacek Biernat, Astrid Nissen, Anne Hofmann, Kai Schönig, Hermann Bujard, Andreas Haemisch^¶, Eckhard Mandelkow, Lepu Zhou^||, Gabriele Rune^||, and Eva-Maria Mandelkow¹

From the Max-Planck Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany, the Center of Molecular Biology (ZMBH), University of Heidelberg, Im Neuenheimer Feld, 69120 Heidelberg, Germany, and the ^||Department of Neuroanatomy and the ^¶Central Animal Facility, University of Hamburg Medical School, Martinistrasse 20, 20146 Hamburg, Germany

Neurofibrillary lesions are characteristic for a group of human diseases, named tauopathies, which are characterized by prominent intracellular accumulations of abnormal filaments formed by the microtubule-associated protein Tau. The tauopathies are accompanied by abnormal changes in Tau protein, including pathological conformation, somatodendritic mislocalization, hyperphosphorylation, and aggregation, whose interdependence is not well understood. To address these issues we have created transgenic mouse lines in which different variants of full-length Tau are expressed in a regulatable fashion, allowing one to switch the expression on and off at defined time points. The Tau variants differ by small mutations in the hexapeptide motifs that control the ability of Tau to adopt a -structure conformation and hence to aggregate. The "pro-aggregation" mutant K280, derived from one of the mutations observed in frontotemporal dementias, aggregates avidly in vitro, whereas the "anti-aggregation" mutant K280/PP cannot aggregate because of two -breaking prolines. In the transgenic mice, the pro-aggregation Tau induces a pathological conformation and pre-tangle aggregation, even at low expression levels, the anti-aggregation mutant does not. This illustrates that abnormal aggregation is primarily controlled by the molecular structure of Tau in vitro and in the organism. Both variants of Tau become mislocalized and hyperphosphorylated independently of aggregation, suggesting that localization and phosphorylation are mainly a consequence of increased concentration. These pathological changes are reversible when the expression of Tau is switched off. The pro-aggregation Tau causes a strong reduction in spine synapses.

Received for publication, June 27, 2007 , and in revised form, August 22, 2007.

^* This research was supported in part by grants from Max-Planck-Gesellschaft and Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. E-mail: mandelkow{at}mpasmb.desy.de.

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