The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-beta 1-40 peptide

Authors

Priyanka Narayan, University of Cambridge
Angel Orte, University of Cambridge
Richard W. Clarke, University of Cambridge
Benedetta Bolognesi, University of Cambridge
Sharon Hook, University of Cambridge
Kristina A. Ganzinger, University of Cambridge
Sarah Meehan, University of Cambridge
Mark R. Wilson, University of WollongongFollow
Christopher M. Dobson, University of CambridgeFollow
David Klenerman, University of Cambridge

RIS ID

47437

Publication Details

Narayan, P., Orte, A., Clarke, R. W., Bolognesi, B., Hook, S., Ganzinger, K. A., Meehan, S., Wilson, M. R., Dobson, C. M. and Klenerman, D. (2012). The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-beta _1-40 peptide. Nature Structural and Molecular Biology, 19 (1), 79-84.

Abstract

In recent genome-wide association studies, the extracellular chaperone protein, clusterin, has been identified as a newly-discovered risk factor in Alzheimer's disease. We have examined the interactions between human clusterin and the Alzheimer's disease-associated amyloid-β _1-40 peptide (Aβ _1-40), which is prone to aggregate into an ensemble of oligomeric intermediates implicated in both the proliferation of amyloid fibrils and in neuronal toxicity. Using highly sensitive single-molecule fluorescence methods, we have found that Aβ _1-40 forms a heterogeneous distribution of small oligomers (from dimers to 50-mers), all of which interact with clusterin to form long-lived, stable complexes. Consequently, clusterin is able to influence both the aggregation and disaggregation of Aβ _1-40 by sequestration of the Aβ oligomers. These results not only elucidate the protective role of clusterin but also provide a molecular basis for the genetic link between clusterin and Alzheimer's disease.