Caffeine Inhibits Tau Aggregation and Destabilizes the Fibril Associated with Chronic Traumatic Encephalopathy: A...

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Chronic traumatic encephalopathy (CTE) is a tauopathy linked to contact sports, characterized by hyperphosphorylated tau protein aggregates.
• Inhibiting tau aggregation or disassembling fibrils is a key therapeutic strategy for CTE.
• Caffeine (CA) has shown potential in vitro to inhibit tau aggregation and disassemble fibrils, but its atomic-level mechanisms are unclear.

Purpose of the Study:

• To elucidate the atomic-level effects and molecular mechanisms of caffeine on tau aggregation.
• To investigate caffeine's interaction with tau monomers, protofibrils, and fibrils using advanced computational simulations.

Main Methods:

• Extensive molecular dynamics simulations, including replica exchange with solute tempering 2 (REST2) and conventional molecular dynamics (CMD), totaling 43.8 μs.
• Simulations focused on tau protein models: R3-R4 tau monomer, protofibril, and fibril, with and without caffeine.

Main Results:

• Caffeine significantly inhibits beta-sheet formation in tau monomers and disrupts the beta-sheet structure in protofibrils, promoting looser conformations.
• Caffeine binds to tau monomers via hydrogen bonding and pi-pi stacking, and to protofibrils through hydrophobic interactions, potentially blocking aggregation cofactors.
• Caffeine destabilizes tau fibrils and reverses the liquid-to-solid phase transition (LSPT) of tau.

Conclusions:

• Caffeine demonstrates a significant atomic-level impact on tau aggregation pathways, inhibiting formation and promoting disassembly.
• The findings provide a theoretical basis for developing caffeine-based or caffeine-inspired drugs for CTE prevention and treatment.
• Caffeine's interaction with tau offers a promising avenue for therapeutic intervention against tauopathies.