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J Biol Chem. 2008 May 16;283(20):13806-16. doi: 10.1074/jbc.M800247200. Epub 2008 Mar 21.

Nucleation-dependent tau filament formation: the importance of dimerization and an estimation of elementary rate constants.

Author information

1
Center for Molecular Neurobiology, Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA.

Abstract

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 approximately 2 tau protomers/beta-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.

PMID:
18359772
PMCID:
PMC2376241
DOI:
10.1074/jbc.M800247200
[Indexed for MEDLINE]
Free PMC Article

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