Approved Parkinson's COMT inhibitors tolcapone and entacapone curb mutant tau aggregation and seeding in human neurons
- Tolcapone and entacapone, approved COMT inhibitors, were tested as modulators of tau aggregation, with attention to the pathogenic P301 mutant form.
- In cell-free assays both compounds blocked aggregation in a dose-dependent way, and P301S tau showed higher sensitivity, tighter binding by SPR and better docking energies than wild type.
- Fibrils grown with either drug triggered less oligomerization and phosphorylation in SH-SY5Y cells, tolcapone being more protective.
- Treating hiPSC-derived neurons after fibril seeding reduced insoluble tau and phosphorylation without obvious toxicity.
💡 Points
What concentration did the cell-free and neuronal dose-responses actually need? If tau suppression sits in the tens of micromolar, free brain exposure at tolerated doses probably won't reach it, and tolcapone's liver liability already narrows the margin. The hiPSC seeding model is a decent human readout, but I'd want a COMT-independent control before believing real tau engagement.