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

Narayan P., Orte A., Clarke R.W., Bolognesi B., Hook S., Ganzinger K.A., Meehan S., Wilson M.R., Dobson C.M., Klenerman D.

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.

Nat. Struct. Mol. Biol. 19:79-83(2011) [PubMed] [Europe PMC]

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