Polymerization of Microtubule-associated Protein Tau under Near-physiological Conditions

Abstract

Neurofibrillary tangles, which form in certain degenerating neurons in the brains of patients with Alzheimer's disease, are amassed from filaments having a straight or paired helical morphology. Solubilization of these filaments reveals that they are composed of the microtubule-associated protein tau. It has not previously been shown, however, that tau will assemble to form filaments of similar morphology under conditions representative of the intracellular environment. We have succeeded in forming such filaments using tau purified from porcine or rat microtubules. The filaments are relatively straight with narrowing at irregular intervals, and are about 10 nm wide, a morphology similar to that of straight filaments seen in Alzheimer's disease neurofibrillary tangles. At tau concentrations of 1-10 M, in vitro assembly occurs at physiological pH, ionic strength, temperature, and reducing potential, and each one of these factors modulates the reaction. Assembly is judged to be only slowly reversible by the exponential rather than normal distribution of filament lengths, and by the limited disassembly observed under conditions which inhibit polymerization. Tau purified directly from whole brain tissue rather than from microtubules does not polymerize under conditions described in this report.

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…In fact, the solubility of Tau in vitro is millimolar, much higher than its concentration in cells ( micromolar), which explains in part why it has taken a long time to discover assembly conditions in vitro ( Fig. 3; Wille et al 1992;Crowther et al 1994;Wilson and Binder 1995). However, two factors contribute to pushing Tau toward aggregation.…”

The fluorescent characterization of the polymerized microtubule-associated protein Tau

“…Some author reported that assembly of microtubule-associated protein tau into Alzheimer-like filaments could be induced by sulphated glycosaminoglycans, especially by heparin [1][2][3][4][5][6][7][8][9][10][11]. We compared the kinetics in the fluorescence formation and in light scattering while tau was incubated with and without heparin ( Table 1).…”

“…Filaments with a straight or paired helical morphology are the major components of the neurofibrillary tangles that form a defining neuropathological characteristic of Alzheimer's disease [1,2]. Solubilization of these filaments reveals that they are composed of the microtubule-associated protein tau [2].…”

“…Solubilization of these filaments reveals that they are composed of the microtubule-associated protein tau [2]. Tau protein plays an important role in neuronal morphogenesis, the maintenance of axonal shape, and axonal transport through its ability to bind and regulate microtubule structure and dynamics [3].…”

Chaperone-Like Manner of Human Neuronal Tau Towards Lactate Dehydrogenase

“…Under some conditions, tau aggregates and forms straight or paired helical filaments (PHFs) that are the major components of NFTS, a totally inactivated form in neuropathological characteristic of AD (26)(27)(28). In this lab, it has been found that tau interacts with d-glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in a chaperone-like manner (29).…”