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J. Biol. Chem., Vol. 281, Issue 2, 1205-1214, January 13, 2006

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Inducible Expression of Tau Repeat Domain in Cell Models of Tauopathy

AGGREGATION IS TOXIC TO CELLS BUT CAN BE REVERSED BY INHIBITOR DRUGS^*

From the Max-Planck-Unit for Structural Molecular Biology, DESY, Notkestrasse 85, 22607 Hamburg, Germany

We generated several cell models of tauopathy in order to study the mechanisms of neurodegeneration in diseases involving abnormal changes of tau protein. N2a neuroblastoma cell lines were created that inducibly express different variants of the repeat domain of tau (tau_RD) when exposed to doxycycline (Tet-On system). The following three constructs were chosen: (i) the repeat domain of tau that coincides with the core of Alzheimer paired helical filaments; (ii) the repeat domain with the deletion mutation K280 known from frontotemporal dementia and highly prone to spontaneous aggregation; and (iii) the repeat domain with K280 and two proline point mutations that inhibit aggregation. The comparison of wild-type, pro-aggregation, and anti-aggregation mutants shows the following. (a) Aggregation of tau_RD is toxic to cells. (b) The degree of aggregation and toxicity depends on the propensity for -structure. (c) Soluble mutants of tau_RD that cannot aggregate are not toxic. (d) Aggregation is preceded by fragmentation. (e) Fragmentation of tau_RD in cells is initially due to a thrombin-like protease activity. (f) Phosphorylation of tau_RD (at KXGS motifs) precedes aggregation but is not correlated with the degree of aggregation. (g) Aggregates of tau_RD disappear when the expression is silenced, showing that aggregation is reversible. (h) Aggregation can be prevented by drugs and even pre-formed aggregates can be dissolved again by drugs. Thus, the cell models open up new insights into the relationship between the structure, expression, phosphorylation, aggregation, and toxicity of tau_RD that can be used to test current hypotheses on tauopathy and to develop drugs that prevent the aggregation and degeneration of cells.

Received for publication, July 18, 2005 , and in revised form, September 22, 2005.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft, Max-Planck-Gesellschaft, and Institute for the Study of Aging. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed. E-mail: mandelkow{at}mpasmb.desy.de.

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