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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biophysics / methods
  • Dimerization
  • Humans
  • Kinetics
  • Microtubules / chemistry
  • Models, Biological
  • Models, Chemical
  • Models, Statistical
  • Normal Distribution
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Temperature
  • Thiazines / pharmacology
  • Time Factors
  • tau Proteins / chemistry*


  • Recombinant Proteins
  • Thiazines
  • tau Proteins