Authors:
Sara García-Viñuales, Rashik Ahmed, Michele Sciacca, Valeria Lanza, Maria Laura Giuffrida, Stefania Zimbone, Valeria Romanucci, Armando Zarrelli, Corrado Bongiorno, Natalia Spinella, Clelia Galati, Giovanni Di Fabio, Giuseppe Melacini, Danilo Milar (...)
Sara García-Viñuales, Rashik Ahmed, Michele Sciacca, Valeria Lanza, Maria Laura Giuffrida, Stefania Zimbone, Valeria Romanucci, Armando Zarrelli, Corrado Bongiorno, Natalia Spinella, Clelia Galati, Giovanni Di Fabio, Giuseppe Melacini, Danilo Milardi
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Abstract:
Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid ? peptide (A?) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (Silybum marianum), has been shown to significantly inhibit A? aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address (...)
Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid ? peptide (A?) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (Silybum marianum), has been shown to significantly inhibit A? aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both A? monomers and oligomers and evidence that silybin may shield the "toxic" surfaces formed by the N-terminal and central hydrophobic regions of A?. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed how even subtle differences in chemical structure may entail different effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin's therapeutic potential.
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