Abstract
Aberrant aggregates of the 42-residue form of the amyloid-β peptide (Aβ(42)) are cytotoxic in Alzheimer's disease (AD). Cost-effective and chronically safe disease-modifying therapeutics are needed to address the AD medical emergency worldwide. To increase our understanding of the mechanisms of Aβ(42)-induced cytotoxicity and to investigate clinically relevant aminosterols, we study the impact of claramine on the aggregation kinetics and properties of Aβ(42) aggregates, as well as the ability of these proteotoxic species to bind and disrupt cell membranes. Whereas previously studied aminosterols accelerated Aβ(42) aggregation, we show that claramine potently inhibits Aβ(42) amyloid fibril formation. We find that claramine stabilizes soluble Aβ(42), speeding up primary and secondary nucleation into species with antiparallel β-sheet structure that are elongation incompetent, thereby depleting Aβ(42) monomers from the aggregation reaction. This steroid-polyamine also dissociates Aβ(42) fibrillar aggregates, resulting in the abrogation of the autocatalytic capacity of Aβ(42) fibrils, and it also inhibits the aggregation of a tau fragment relevant to AD. Upon exposure of human neuroblastoma cells to stabilized Aβ(42) oligomers, claramine effectively neutralized Aβ(42) oligomer-induced cytotoxicity by preventing their binding to cell membranes. Owing to the unique mechanism of action of aminosterols to reduce the toxicity of soluble Aβ(42) aggregates by protecting cell membranes, and the newly characterized ability of claramine to inhibit Aβ(42) fibril formation and dissociate fibrillar Aβ(42) resulting in the interruption of the positive feedback loop in Aβ(42) aggregation, our findings further emphasize the relevance of this family of natural products as potential treatments for AD and other protein misfolding diseases.