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

Marten Beeg, Matteo Stravalaci, Margherita Romeo, Arianna Dorotea Carrá, Alfredo Cagnotto, Alessandro Rossi, Luisa Diomede, Mario Salmona, Marco Gobbi

Research output: Contribution to journalArticlepeer-review

Abstract

The aggregation of amyloid β protein (Aβ) is a fundamental pathogenic mechanism leading to the neuronal damage present in Alzheimer 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.Wecharacterized 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=1nM) 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 prevent 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 neuroprotective effects of the chaperone.

Original languageEnglish
Pages (from-to)6958-6966
Number of pages9
JournalJournal of Biological Chemistry
Volume291
Issue number13
DOIs
Publication statusPublished - Mar 25 2016

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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