Quantitative Attribution of the Protective Effects of Aminosterols against Protein Aggregates to Their Chemical Structures and Ability to Modulate Biological Membranes

Natural aminosterols are promising drug candidates againstneurodegenerativediseases, like Alzheimer and Parkinson, and one relevant protectivemechanism occurs via their binding to biological membranes and displacementor binding inhibition of amyloidogenic proteins and their cytotoxicoligomers. We compared three chemically different aminosterols, findingthat they exhibited different (i) binding affinities, (ii) chargeneutralizations, (iii) mechanical reinforcements, and (iv) key lipidredistributions within membranes of reconstituted liposomes. Theyalso had different potencies (EC50) in protecting culturedcell membranes against amyloid-& beta; oligomers. A global fittinganalysis led to an analytical equation describing quantitatively theprotective effects of aminosterols as a function of their concentrationand relevant membrane effects. The analysis correlates aminosterol-mediatedprotection with well-defined chemical moieties, including the polyaminegroup inducing a partial membrane-neutralizing effect (79 & PLUSMN; 7%)and the cholestane-like tail causing lipid redistribution and bilayermechanical resistance (21 & PLUSMN; 7%), linking quantitatively theirchemistry to their protective effects on biological membranes.