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J. Biol. Chem., Vol. 280, Issue 5, 3963-3973, February 4, 2005

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Changed Conformation of Mutant Tau-P301L Underlies the Moribund Tauopathy, Absent in Progressive, Nonlethal Axonopathy of Tau-4R/2N Transgenic Mice^*

Dick Terwel, Reena Lasrado, Johan Snauwaert¶, Erno Vandeweert¶, Chris Van Haesendonck¶, Peter Borghgraef, and Fred Van Leuven||

From the Experimental Genetics Group, Department of Human Genetics, KU Leuven, B-3000 Leuven, Belgium and the ^¶Laboratory of Solid State Physics and Magnetism, KU Leuven, B-3001 Leuven, Belgium

Protein tau-3R/4R isoform ratio and phosphorylation regulates binding to microtubules and, when disturbed by aging or mutations, results in diverse tauopathies and in neurodegeneration. The underlying mechanisms were studied here in three transgenic mouse strains with identical genetic background, all expressing the tau-4R/2N isoform driven specifically in neurons by the thy1 gene promoter. Two strains, expressing human tau-4R/2N or mutant tau-4R/2N-P301L at similar, moderate levels, developed very different phenotypes. Tau-4R/2N mice became motor-impaired already around age 6–8 weeks, accompanied by axonopathy (dilatations, spheroids), but no tau aggregates, and surviving normally. In contrast, tau-P301L mice developed neurofibrillary tangles from age 6 months, without axonal dilatations and, despite only minor motor problems, all succumbing before the age of 13 months. The third strain, obtained by tau knock-out/knock-in (tau-KOKI), expressed normal levels of wild-type human tau-4R/2N replacing all mouse tau isoforms. Tau-KOKI mice survived normally with minor motor problems late in life and without any obvious pathology. Biochemically, a fraction of neuronal tau in aging tau-P301L mice was hyperphosphorylated concomitant with conformational changes and aggregation, but overall, tau-4R/2N was actually more phosphorylated than tau-P301L. Significantly, tau with changed conformation and with hyperphosphorylation colocalized in the same neurons in aging tau-P301L mice. Taken together, we conclude that excessive binding of tau-4R/2N as opposed to reduced binding of tau-P301L to microtubules is responsible for the development of axonopathy and tauopathy, respectively, in tau-4R/2N and tau-P301L mice and that the conformational change of tau-P301L is a major determinant in triggering the tauopathy.

Received for publication, August 27, 2004 , and in revised form, October 20, 2004.

^* This work was supported by Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, the European Economic Community (EEC) 5th Framework Program, the Rooms-fund, the KU Leuven Research Fund and KU Leuven-R&D, the Instituut voor Aanmoediging van Wetenschappelijk en Technisch Onderzoek, the European Space Agency, and the EEC Marie Curie Training Site of the EURON Ph.D. School for Neurosciences. 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.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Experimental Genetics Group-LEGT_EGG, Dept. Human Genetics, KU Leuven-Campus Gasthuisberg O&N 06, B-3000 Leuven, Belgium. Tel.: 32-16-34-58-88; Fax: 32-16-34-58-71; E-mail: fredvl{at}med.kuleuven.ac.be.

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