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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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4-Amino-3',4'-dihydroxychalcone Increases Tau Dynamics in Phase-Separated Droplets and Inhibits Tau Aggregation.
Rajeshkumar S Gop1, Rishav Adhikary1, Anuradha Venkatramani1
1Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra 400076, India.
ACS Chemical Neuroscience
|April 14, 2025
Summary
4-Amino-3
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Microtubule-associated protein tau aggregation is central to neurodegenerative diseases like Alzheimer's.
- Small molecules are explored as therapeutic agents to inhibit tau aggregation.
Purpose of the Study:
- To identify and characterize novel inhibitors of tau aggregation.
- To evaluate the potential of 4-Amino-3',4'-dihydroxychalcone (4-ADHC) as a therapeutic agent for tauopathies.
Main Methods:
- Surface plasmon resonance to determine binding affinity.
- Spectroscopic and microscopic techniques (SEC, fluorescence, AFM, DLS) to assess tau aggregation stages.
- In vitro assays for heparin/arachidonic acid-induced tau aggregation and tubulin polymerization.
Main Results:
- 4-ADHC binds to tau with a dissociation constant of 5.1 ± 0.8 μM.
- 4-ADHC inhibits tau liquid-liquid phase separation, oligomerization, and filamentation.
- The compound enhances tau dynamics in phase-separated droplets, preventing maturation.
- 4-ADHC shows no inhibitory effect on tubulin polymerization or unrelated enzymes.
Conclusions:
- 4-ADHC is a potent inhibitor of multiple stages of tau aggregation.
- The compound's ability to disrupt tau pathology makes it a promising candidate for developing new treatments for neurodegenerative diseases.
