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  3. Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology

Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology

  • Nat Commun. 2023 Sep 6;14(1):5444. doi: 10.1038/s41467-023-41241-6.
Yongqi Huang # 1,  Jitao Wen # 2 3,  Lisa-Marie Ramirez 4,  Eymen Gümüşdil 4 5,  Pravin Pokhrel 6,  Viet H Man 7,  Haiqiong Ye 8,  Yue Han 8,  Yunfei Liu 8,  Ping Li 8,  Zhengding Su 8,  Junmei Wang 7,  Hanbin Mao 6,  Markus Zweckstetter 4 9,  Sarah Perrett 2 3,  Si Wu 10 11,  Meng Gao 12
Affiliations

Affiliations

  • 1 Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, 430068, Wuhan, China. yqhuang@hbut.edu.cn.
  • 2 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
  • 3 University of the Chinese Academy of Sciences, 100049, Beijing, China.
  • 4 German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
  • 5 Department of Molecular Biology and Genetics, Gebze Technical University, 41400, Gebze Çayirova, Kocaeli, Turkey.
  • 6 Department of Chemistry & Biochemistry, Advanced Materials and Liquid Crystal Institute, Department of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
  • 7 Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • 8 Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, 430068, Wuhan, China.
  • 9 Department for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077, Göttingen, Germany.
  • 10 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China. wusi@ibp.ac.cn.
  • 11 University of the Chinese Academy of Sciences, 100049, Beijing, China. wusi@ibp.ac.cn.
  • 12 Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, 430068, Wuhan, China. gaomeng@hbut.edu.cn.
  • # Contributed equally.
PMID: 37673952 DOI: 10.1038/s41467-023-41241-6
Abstract

Preventing tau aggregation is a potential therapeutic strategy in Alzheimer's disease and Other tauopathies. Recently, liquid-liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid-liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.

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