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

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.

• Authors: Priyanka Narayan, Angel Orte, Richard W Clarke, Benedetta Bolognesi, Sharon Hook, Kristina A Ganzinger, Sarah Meehan, Mark R Wilson, Christopher M Dobson, David Klenerman
• Journal: Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 19 Issue 1 Pg. 79-83 (Dec 18 2011) ISSN: 1545-9985 [Electronic] United States
• PMID: 22179788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Clusterin
• Molecular Chaperones
• Peptide Fragments
• amyloid beta-protein (1-40)

Topics

• Algorithms
• Alzheimer Disease (metabolism)
• Amyloid (chemistry, metabolism, ultrastructure)
• Amyloid beta-Peptides (chemistry, metabolism)
• Clusterin (chemistry, metabolism)
• Extracellular Space (metabolism)
• Fluorescence
• Fluorometry (instrumentation, methods)
• Humans
• Kinetics
• Microscopy, Confocal
• Microscopy, Electron, Transmission
• Molecular Chaperones (chemistry, metabolism)
• Peptide Fragments (chemistry, metabolism)
• Protein Binding
• Protein Multimerization
• Thermodynamics