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.


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.

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