Amyloid-β Oligomers are Sequestered by both Intracellular and Extracellular Chaperones

The aberrant aggregation of the amyloid-beta peptide into beta-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 A beta 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-beta(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 A beta in senile plaques. One of the chaperones, alpha beta-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 A beta oligomers. This conclusion suggests that these chaperones, both of which are ATP-independent, are able to inhibit potentially pathogenic A beta oligomer-associated processes whether they occur in the extracellular or intracellular environment.