Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

• Published in: The Journal of biological chemistry Vol. 281; no. 44; pp. 33182 - 33191
• Main Authors: Evans, Christopher G., Wisén, Susanne, Gestwicki, Jason E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.11.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Adenosine Triphosphatases - metabolism; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - ultrastructure; HSP40 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - agonists; HSP70 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - ultrastructure; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - ultrastructure; Humans; Microscopy, Electron, Transmission; Peptide Fragments - metabolism; Peptide Fragments - ultrastructure; Protein Binding; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M606192200

Alzheimer disease is a neurological disorder that is characterized by the presence of fibrils and oligomers composed of the amyloid β (Aβ) peptide. In models of Alzheimer disease, overexpression of molecular chaperones, specifically heat shock protein 70 (Hsp70), suppresses phenotypes related to Aβ aggregation. These observations led to the hypothesis that chaperones might interact with Aβ and block self-association. However, although biochemical evidence to support this model has been collected in other neurodegenerative systems, the interaction between chaperones and Aβ has not been similarly explored. Here, we examine the effects of Hsp70/40 and Hsp90 on Aβ aggregation in vitro. We found that recombinant Hsp70/40 and Hsp90 block Aβ self-assembly and that these chaperones are effective at substoichiometric concentrations (∼1:50). The anti-aggregation activity of Hsp70 can be inhibited by a nonhydrolyzable nucleotide analog and encouraged by pharmacological stimulation of its ATPase activity. Finally, we were interested in discerning what type of amyloid structures can be acted upon by these chaperones. To address this question, we added Hsp70/40 and Hsp90 to pre-formed oligomers and fibrils. Based on thioflavin T reactivity, the combination of Hsp70/40 and Hsp90 caused structural changes in oligomers but had little effect on fibrils. These results suggest that if these chaperones are present in the same cellular compartment in which Aβ is produced, Hsp70/40 and Hsp90 may suppress the early stages of self-assembly. Thus, these results are consistent with a model in which pharmacological activation of chaperones might have a favorable therapeutic effect on Alzheimer disease.