Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Tau protein aggregation is a key hallmark of neurodegenerative diseases such as Alzheimer's disease.
• Inhibiting or reversing tau aggregation presents a potential therapeutic strategy.
• Fungal natural products are a valuable source of bioactive compounds.

Purpose of the Study:

• To investigate the potential of fungal azaphilone derivatives in inhibiting and disassembling tau protein aggregates.
• To identify novel compounds for therapeutic intervention in tauopathies.

Main Methods:

• Screening of Aspergillus nidulans secondary metabolites for tau aggregation inhibitors.
• In vitro testing of 11 azaphilone derivatives for tau assembly inhibition.
• Evaluation of the ability of compounds to disassemble pre-formed tau aggregates.
• Assessment of the impact of potent compounds on tau's microtubule stabilization function.

Main Results:

• All 11 tested azaphilone derivatives inhibited tau filament assembly in vitro.
• Four derivatives demonstrated dose-dependent disassembly of pre-formed tau aggregates.
• These compounds reduced the total length and number of tau polymers.
• The most potent compounds did not completely inhibit tau-mediated microtubule assembly.

Conclusions:

• Azaphilone derivatives represent a new class of anti-tau aggregation compounds with a novel structural scaffold.
• These compounds are promising lead candidates for developing therapeutics that inhibit tau aggregation and disassemble existing tau filaments.
• The findings suggest a potential new treatment strategy for tauopathies.