Inhibition of tau filament formation by conformational modulation.
Antiaggregation drugs play an important role in therapeutic approaches for Alzheimer's disease. Although a large number of small molecules that inhibit the aggregation of the tau protein have been identified, little is known about their mode of action. Here, we reveal the mechanism and the nature of tau species that are generated by interaction of tau with the organic compound pthalocyanine tetrasulfonate (PcTS). We demonstrate that PcTS interferes with tau filament formation by targeting the protein into soluble oligomers. A combination of NMR spectroscopy, electron paramagnetic resonance, and small-angle X-ray scattering reveals that the soluble tau oligomers contain a dynamic, noncooperatively stabilized core with a diameter of 30-40 nm that is distinct from the core of tau filaments. Our results suggest that specific modulation of the conformation of tau is a viable strategy for reduction of pathogenic tau deposits.
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Elias
E
Akoury
Michal
M
Gajda
Marcus
M
Pickhardt
Jacek
J
Biernat
Pornsuwan
P
Soraya
Christian
C
Griesinger
Eckhard
E
Mandelkow
Markus
M
Zweckstetter
D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D017550:Spectroscopy, Fourier Transform Infrared; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D007211:Indoles; D016875:tau Proteins; C028418:tetrasulfophthalocyanine