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

Journal Article


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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. © 2012 Nature America, Inc. All rights reserved.

Authors


  •   Narayan, Priyanka (external author)
  •   Orte, A (external author)
  •   Clarke, Richard W. (external author)
  •   Bolognesi, Benedetta (external author)
  •   Hook, S (external author)
  •   Ganzinger, K A. (external author)
  •   Meehan, Sarah (external author)
  •   Mark R Wilson
  •   Dobson, Christopher M. (external author)
  •   Klenerman, David (external author)

Publication Date


  • 2012

Citation


  • Narayan, P., Orte, A., Clarke, R. W., Bolognesi, B., Hook, S., Ganzinger, K. A., Meehan, S., Wilson, M. R., Dobson, C. M. & Klenerman, D. (2012). The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β 1-40 peptide. Nature Structural and Molecular Biology, 19 (1), 79-83.

Scopus Eid


  • 2-s2.0-84855450514

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=6401&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/3059

Has Global Citation Frequency


Number Of Pages


  • 4

Start Page


  • 79

End Page


  • 83

Volume


  • 19

Issue


  • 1

Place Of Publication


  • United States

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. © 2012 Nature America, Inc. All rights reserved.

Authors


  •   Narayan, Priyanka (external author)
  •   Orte, A (external author)
  •   Clarke, Richard W. (external author)
  •   Bolognesi, Benedetta (external author)
  •   Hook, S (external author)
  •   Ganzinger, K A. (external author)
  •   Meehan, Sarah (external author)
  •   Mark R Wilson
  •   Dobson, Christopher M. (external author)
  •   Klenerman, David (external author)

Publication Date


  • 2012

Citation


  • Narayan, P., Orte, A., Clarke, R. W., Bolognesi, B., Hook, S., Ganzinger, K. A., Meehan, S., Wilson, M. R., Dobson, C. M. & Klenerman, D. (2012). The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β 1-40 peptide. Nature Structural and Molecular Biology, 19 (1), 79-83.

Scopus Eid


  • 2-s2.0-84855450514

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=6401&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/3059

Has Global Citation Frequency


Number Of Pages


  • 4

Start Page


  • 79

End Page


  • 83

Volume


  • 19

Issue


  • 1

Place Of Publication


  • United States