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Type: Journal article
Title: Amyloid-β oligomers are sequestered by both intracellular and extracellular chaperones
Other Titles: Amyloid-beta oligomers are sequestered by both intracellular and extracellular chaperones
Author: Narayan, P.
Meehan, S.
Carver, J.
Wilson, M.
Dobson, C.
Klenerman, D.
Citation: Biochemistry, 2012; 51(46):9270-9276
Publisher: Amer Chemical Soc
Issue Date: 2012
ISSN: 0006-2960
Statement of
Priyanka Narayan, Sarah Meehan, John A. Carver, Mark R. Wilson, Christopher M. Dobson, and David Klenerman
Abstract: The aberrant aggregation of the amyloid-β peptide into β-sheet rich, fibrillar structures proceeds via a heterogeneous ensemble of oligomeric intermediates that have been associated with neurotoxicity in Alzheimer's disease (AD). Of particular interest in this context are the mechanisms by which molecular chaperones, part of the primary biological defenses against protein misfolding, influence Aβ aggregation. We have used single-molecule fluorescence techniques to compare the interactions between distinct aggregation states (monomers, oligomers, and amyloid fibrils) of the AD-associated amyloid-β(1-40) peptide, and two molecular chaperones, both of which are upregulated in the brains of patients with AD and have been found colocalized with Aβ in senile plaques. One of the chaperones, αB-crystallin, is primarily found inside cells, while the other, clusterin, is predominantly located in the extracellular environment. We find that both chaperones bind to misfolded oligomeric species and form long-lived complexes, thereby preventing both their further growth into fibrils and their dissociation. From these studies, we conclude that these chaperones have a common mechanism of action based on sequestering Aβ oligomers. This conclusion suggests that these chaperones, both of which are ATP-independent, are able to inhibit potentially pathogenic Aβ oligomer-associated processes whether they occur in the extracellular or intracellular environment.
Keywords: Brain; Humans; Alzheimer Disease; Molecular Chaperones; Amyloid beta-Peptides
Rights: Copyright © 2012 American Chemical Society
RMID: 0020123178
DOI: 10.1021/bi301277k
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Appears in Collections:Chemistry publications

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