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

Yongqi Huang (), Jitao Wen, Lisa-Marie Ramirez, Eymen Gümüşdil, Pravin Pokhrel, Viet H. Man, Haiqiong Ye, Yue Han, Yunfei Liu, Ping Li, Zhengding Su, Junmei Wang, Hanbin Mao, Markus Zweckstetter, Sarah Perrett, Si Wu () and Meng Gao ()
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Yongqi Huang: Hubei University of Technology
Jitao Wen: Chinese Academy of Sciences
Lisa-Marie Ramirez: German Center for Neurodegenerative Diseases (DZNE)
Eymen Gümüşdil: German Center for Neurodegenerative Diseases (DZNE)
Pravin Pokhrel: Kent State University
Viet H. Man: University of Pittsburgh
Haiqiong Ye: Hubei University of Technology
Yue Han: Hubei University of Technology
Yunfei Liu: Hubei University of Technology
Ping Li: Hubei University of Technology
Zhengding Su: Hubei University of Technology
Junmei Wang: University of Pittsburgh
Hanbin Mao: Kent State University
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)
Sarah Perrett: Chinese Academy of Sciences
Si Wu: Chinese Academy of Sciences
Meng Gao: Hubei University of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41241-6

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