title: 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.affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Narayan
authors.forename: Angel
authors.initials: A
authors.lastname: Orte
authors.forename: Richard W
authors.initials: RW
authors.lastname: Clarke
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bolognesi
authors.forename: Sharon
authors.initials: S
authors.lastname: Hook
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Ganzinger
authors.forename: Sarah
authors.initials: S
authors.lastname: Meehan
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wilson
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: David
authors.initials: D
authors.lastname: Klenerman
mesh_terms: D000465:Algorithms; D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D051152:Clusterin / Q000737:chemistry / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D005453:Fluorescence; D005470:Fluorometry / Q000295:instrumentation / Q000379:methods; D006801:Humans; D007700:Kinetics; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D051152:Clusterin; D018832:Molecular Chaperones; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)