An aminosterol breaks the autocatalytic cycle of Aβ$_{42}$ aggregation and protects cell membranes from its soluble aggregates

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.