An aminosterol breaks the autocatalytic cycle of Aβ₄₂ aggregation and protects cell membranes from its soluble aggregates.

ABSTRACT: Aberrant aggregates of the 42-residue form of the amyloid-β peptide (Aβ₄₂) 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 Aβ₄₂-induced cytotoxicity and to investigate clinically relevant aminosterols, we study the impact of claramine on the aggregation kinetics and properties of Aβ₄₂ aggregates, as well as the ability of these proteotoxic species to bind and disrupt cell membranes. Whereas previously studied aminosterols accelerated Aβ₄₂ aggregation, we show that claramine potently inhibits Aβ₄₂ amyloid fibril formation. We find that claramine stabilizes soluble Aβ₄₂, speeding up primary and secondary nucleation into species with antiparallel β-sheet structure that are elongation incompetent, thereby depleting Aβ₄₂ monomers from the aggregation reaction. This steroid-polyamine also dissociates Aβ₄₂ fibrillar aggregates, resulting in the abrogation of the autocatalytic capacity of Aβ₄₂ fibrils, and it also inhibits the aggregation of a tau fragment relevant to AD. Upon exposure of human neuroblastoma cells to stabilized Aβ₄₂ oligomers, claramine effectively neutralized Aβ₄₂ 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 Aβ₄₂ aggregates by protecting cell membranes, and the newly characterized ability of claramine to inhibit Aβ₄₂ fibril formation and dissociate fibrillar Aβ₄₂ resulting in the interruption of the positive feedback loop in Aβ₄₂ aggregation, our findings further emphasize the relevance of this family of natural products as potential treatments for AD and other protein misfolding diseases.

SUBMITTER: Fallot LB 

PROVIDER: S-EPMC12280974 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature