Electric field-induced destabilization and surface modulation of Aβ42 fibrils in molecular simulations: theoretical...

The amyloid-β peptide 42 (Aβ42) forms fibrillar aggregates that are a hallmark of Alzheimer's disease. While recent therapeutic strategies targeting Aβ42 fibrils and oligomers have shown promise, safer and more effective interventions are still needed. Noninvasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have emerged as potential complementary approaches, yet the molecular mechanisms by which electric fields influence amyloid aggregation remain poorly understood.

We performed atomistic molecular dynamics simulations to investigate the response of Aβ42 fibrils to static electric fields of increasing strength. Simulations were based on an ex vivo fibril structure with reconstructed N-terminal regions, and different structural restraint conditions were used to disentangle surface and core effects.

Electric fields perturb the disordered N-terminal 'fuzzy coat', altering its conformational dynamics and weakening its interactions with the fibril core, thereby modifying the fibril surface properties. Simulations with unrestrained fibril ends further reveal increased fluctuations in core residues, indicating field-induced destabilization that may hinder elongation.

These findings provide molecular-level insight into how static electric fields can modulate amyloid fibril formation and propagation, offering a possible mechanistic basis for the effects of tDCS and related brain stimulation techniques.