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Clusterin binds to Aβ1-42 oligomers with high affinity and interferes with peptide aggregation by inhibiting primary and secondary nucleation.

著者 Beeg M , Stravalaci M , Romeo M , Carra AD , Cagnotto A , Rossi A , Diomede L , Salmona M , Gobbi M
J Biol Chem.2016 Feb 16 ; ():.
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The aggregation of amyloid β-protein (Aβ) is a fundamental pathogenic mechanism leading to the neuronal damage present in Alzheimer's disease, and soluble Aβ oligomers are thought to be a major toxic culprit. Thus, better knowledge and specific targeting of the pathways that lead to these noxious species may result in valuable therapeutic strategies. We have characterized some effects of the molecular chaperone clusterin, providing new and more detailed evidence of its potential neuroprotective effects. Using a classical Thioflavin T assay, we observed a dose-dependent inhibition of the aggregation process. The global analysis of time-courses under different conditions demonstrated that clusterin has no effect on the elongation rate but mainly interferes with the nucleation processes (both primary and secondary), reducing the number of nuclei available for further fibril growth. Then, using a recently developed immunoassay based on Surface Plasmon Resonance, we obtained direct evidence of a high affinity (KD = 1 nM) interaction of clusterin with biologically relevant Aβ1-42 oligomers, selectively captured on the sensor chip. Moreover, with the same technology, we observed that substoichiometric concentrations of clusterin prevents oligomer interaction with the antibody 4G8, suggesting that the chaperone shields hydrophobic residues exposed on the oligomeric assemblies. Finally, we found that preincubation with clusterin antagonizes the toxic effects of Aβ1-42 oligomers, as evaluated in a recently developed in vivo model in Caenorhabditis elegans. These data substantiate the interaction of clusterin with biologically active regions exposed on nuclei/oligomers of Aβ1-42, providing a molecular basis for the chaperone's neuroprotective effects.
PMID: 26884339 [PubMed - as supplied by publisher]
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