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J. Biol. Chem., Vol. 283, Issue 20, 13806-13816, May 16, 2008

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Nucleation-dependent Tau Filament Formation

THE IMPORTANCE OF DIMERIZATION AND AN ESTIMATION OF ELEMENTARY RATE CONSTANTS^*

Erin E. Congdon¹², Sohee Kim¹, Jonathan Bonchak, Tanakorn Songrug, Anastasios Matzavinos, and Jeff Kuret³

From the Center for Molecular Neurobiology, Department of Molecular and Cellular Biochemistry and the Mathematical Biosciences Institute, Department of Mathematics, The Ohio State University, Columbus, Ohio 43210

Filamentous inclusions composed of the microtubule-associated protein tau are found in Alzheimer disease and other tauopathic neurodegenerative diseases, but the mechanisms underlying their formation from full-length protein monomer under physiological conditions are unclear. To address this issue, the fibrillization of recombinant full-length four-repeat human tau was examined in vitro as a function of time and submicromolar tau concentrations using electron microscopy assay methods and a small-molecule inducer of aggregation, thiazine red. Data were then fit to a simple homogeneous nucleation model with rate constant constraints established from filament dissociation rate, critical concentration, and mass-per-unit length measurements. The model was then tested by comparing the predicted time-dependent evolution of length distributions to experimental data. Results indicated that once assembly-competent conformations were attained, the rate-limiting step in the fibrillization pathway was tau dimer formation. Filament elongation then proceeded by addition of tau monomers to nascent filament ends. Filaments isolated at reaction plateau contained 2 tau protomers/β-strand spacing on the basis of mass-per-unit length measurements. The model suggests four key steps in the aggregation pathway that must be surmounted for tau filaments to form in disease.

Received for publication, January 10, 2008 , and in revised form, March 20, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant AG14452. This work was also supported by Alzheimer's Association Grant IIRG-05-14288. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Movie 1.

¹ Both authors contributed equally to this work.

² Present address: Taub Institute, Columbia University, New York, NY 10032.

³ To whom correspondence should be addressed: Center for Molecular Neurobiology, 1060 Carmack Rd., Columbus, OH 43210. Tel.: 614-688-5899; Fax: 614-292-5379; E-mail: kuret.3{at}osu.edu.

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