Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 19, Issue 1, Pages 79-U97Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2191
Keywords
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Funding
- Marshall Aid Commemoration Commission
- National Science Foundation
- European Union
- Christ's College
- Alzheimer's Research Trust
- Biotechnology and Biological Sciences Research Council
- Engineering and Physical Sciences Research Council
- Royal Society
- Australian Research Council [DP0773555, DP0984341]
- Wellcome Trust
- Medical Research Council
- Augustus Newman Foundation
- Studienstiftung des deutschen Volkes
- Medical Research Council [MC_G1000734] Funding Source: researchfish
- MRC [MC_G1000734] Funding Source: UKRI
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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-beta(1-40) peptide (A beta(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 A beta(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 A beta(1-40) by sequestration of the Ab 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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