Electric Field-Induced Destabilization and Surface Modulation of Aβ42 Fibrils in Molecular Simulations: Theoretical Implications for DC Stimulation in Alzheimer's Disease
The amyloid-{beta} peptide 42 (A{beta}42) forms fibrillar aggregates that are a hallmark of Alzheimers disease. While recent pharmacologic therapeutic strategies targeting A{beta}42 fibrils and oligomers have shown promising results, safer and more effective approaches are still needed. Non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been increasingly explored as a possible complementary intervention, but the molecular mechanisms by which static electric fields could influence amyloid aggregation remain poorly understood. Here, we use atomistic molecular dynamics simulations to investigate the effects of static electric fields on A{beta}42 fibrils. We examine the response of an ex vivo fibril structure, with reconstructed N-terminal regions, to increasing field strengths under different structural restraint conditions. Our results show that the electric field perturbs the disordered N-terminal "fuzzy coat," altering its conformational dynamics and reducing its interactions with the fibril core. This reorganization modifies the surface properties of the fibril, potentially impairing secondary nucleation. Additionally, simulations with unrestrained fibril ends reveal increased fluctuations in core residues, particularly near the N-terminus, indicating a destabilizing effect that may hinder fibril elongation. While the field strengths used here exceed those typical of NIBS, our findings provide a molecular-level rationale for how electric fields could modulate fibril propagation and support further experimental investigations under physiologically relevant conditions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/678267v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@9b6a01org.highwire.dtl.DTLVardef@14ca26forg.highwire.dtl.DTLVardef@3c42ccorg.highwire.dtl.DTLVardef@458b4f_HPS_FORMAT_FIGEXP M_FIG C_FIG