Epinephrine destabilizes Alzheimer's disease-related tau protofibril and fibril: a computational study

The aggregation of hyperphosphorylated tau protein into neurofibrillary tangles (NFTs) is associated with Alzheimer's disease (AD). Inhibiting tau aggregation or disrupting preformed fibrillar aggregates may be legitimate therapeutic approaches for AD. Epinephrine, also known as adrenaline, is an endogenous small molecule secreted by the adrenal medulla and can be stimulated by resistance exercise. It was proved to inhibit tau aggregation <i>in vitro</i>. However, atomic insights into the influence of EP on the AD-related tau remain largely unclear. In this work, we performed all-atom molecular dynamics (MD) simulations on the R3-R4 (the third and fourth repeat) tau protofibril and fibril associated with AD, without and with EP molecules. The results reveal that EP can increase the structural instability and flexibility of the R3-R4 protofibril, and elicit a β-sheet-to-coil transformation and loosely-packed conformation. More importantly, EP remodels the K353-D358 salt-bridges that play a vital role in stabilizing the protofibril configuration. Binding analysis determines that EP binds with the protofibril preferentially through hydrophobic, hydrogen-bonding (H-bonding), π-π stacking and cation-π interactions. On the other hand, EP destabilizes and may reverse a liquid-to-solid phase transition (LSPT) of the AD-related tau fibril. The binding modes of EP with the fibrils exhibit differences to those with the protofibrils. By disclosing these findings, our work provides helpful clues for drug candidate design and exercise therapy for treating AD.