Digoxin Inhibits Bax∆2-induced Neuronal Cell Death

Abstract Pro-death Bax isoform BaxΔ2 forms protein aggregates in Alzheimer’s neurons, triggering stress granule formation and neuronal cell death. In seeking chemical ligands to prevent BaxΔ2 monomer aggregation, we performed in silico screening of FDA-approved drugs using computational docking. This screening identified a group of compounds that bind to the hydrophobic pocket of BaxΔ2. Subsequent wet-lab testing revealed that digoxin could block neuronal cell death at nanomolar concentrations (50 to 100 nM). Importantly, digoxin’s protective role is specific to BaxΔ2-induced cell death and is independent of its primary cardio-action on Na/K-ATPase. Further investigation suggests that digoxin does not significantly affect the formation of BaxΔ2 aggregates but may instead modulate BaxΔ2 protein levels. Although the therapeutic use of digoxin for Alzheimer’s disease is not feasible due to its narrow therapeutic window and toxicity, these findings open the door for chemical modification of digoxin, or development of similar compounds, to prevent BaxΔ2-mediated neuronal cell death in Alzheimer’s disease. Competing Interest Statement The authors have declared no competing interest. Footnotes Fixed some typo, symbol, and figure labels