Inhibition of Tau Filament Formation by Conformational Modulation

详细信息    查看全文

• 作者：Elias Akoury ; Michal Gajda ; Marcus Pickhardt ; Jacek Biernat ; Pornsuwan Soraya ; Christian Griesinger ; Eckhard Mandelkow ; Markus Zweckstetter
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：February 20, 2013
• 年：2013
• 卷：135
• 期：7
• 页码：2853-2862
• 全文大小：592K
• 年卷期：v.135,no.7(February 20, 2013)
• ISSN：1520-5126

文摘

Antiaggregation drugs play an important role in therapeutic approaches for Alzheimer鈥檚 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鈥?0 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.