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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:p>\n                    Aberrant aggregates of the 42-residue form of the amyloid-\u03b2 peptide (A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    ) are cytotoxic in Alzheimer\u2019s 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 A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    -induced cytotoxicity and to investigate clinically relevant aminosterols, we study the impact of claramine on the aggregation kinetics and properties of A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    aggregates, as well as the ability of these proteotoxic species to bind and disrupt cell membranes. Whereas previously studied aminosterols accelerated A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    aggregation, we show that claramine potently inhibits A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    amyloid fibril formation. We find that claramine stabilizes soluble A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    , speeding up primary and secondary nucleation into species with antiparallel \u03b2-sheet structure that are elongation incompetent, thereby depleting A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    monomers from the aggregation reaction. This steroid\u2013polyamine also dissociates A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    fibrillar aggregates, resulting in the abrogation of the autocatalytic capacity of A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    fibrils, and it also inhibits the aggregation of a tau fragment relevant to AD. Upon exposure of human neuroblastoma cells to stabilized A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    oligomers, claramine effectively neutralized A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    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 A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    aggregates by protecting cell membranes, and the newly characterized ability of claramine to inhibit A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    fibril formation and dissociate fibrillar A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    resulting in the interruption of the positive feedback loop in A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    aggregation, our findings further emphasize the relevance of this family of natural products as potential treatments for AD and other protein misfolding diseases.\n                  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