Yao, Q.; Sorescu, J. M.; Amin, I. N.; Julian, A.; Heo, J.; Philoctete, D.; Minh, D.; Xiang, J.

Pro-death Bax isoform Bax{Delta}2 forms protein aggregates in Alzheimer's neurons, triggering stress granule formation and neuronal cell death. In seeking chemical ligands to prevent Bax{Delta}2 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 Bax{Delta}2. 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 Bax{Delta}2-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 Bax{Delta}2 aggregates but may instead modulate Bax{Delta}2 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 Bax{Delta}2 mediated neuronal cell death in Alzheimer's disease.