Journal
ACS CHEMICAL NEUROSCIENCE
Volume 10, Issue 8, Pages 3565-3574Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.9b00183
Keywords
Amyloid aggregation; inhibition mechanisms; Alzheimer's disease treatment; molecular chaperones; chaperonin; structural evolution; hydrophobic regions; ANS dye
Funding
- Italian grant FIRB Future in research [RBFR12SIPT]
Ask authors/readers for more resources
Alzheimer's disease is a chronic neurodegenerative disease characterized by the accumulation of pathological aggregates of amyloid beta peptide. Many efforts have been focused on understanding peptide aggregation pathways and on identification of molecules able to inhibit aggregation in order to find an effective therapy. As a result, interest in neuroprotective proteins, such as molecular chaperones, has increased as their normal function is to assist in protein folding or to facilitate the disaggregation and/or clearance of abnormal aggregate proteins. Using biophysical techniques, we evaluated the effects of two chaperones, human Hsp60 and bacterial GroEL, on the fibrillogenesis of A beta(1-42). Both chaperonins interfere with A beta(1-42) aggregation, but the effect of Hsp60 is more significant and correlates with its more pronounced flexibility and stronger interaction with ANS, an indicator of hydrophobic regions. Dose-dependent ThT fluorescence kinetics and SAXS experiments reveal that Hsp60 does not change the nature of the molecular processes stochastically leading to the formation of seeds, but strongly delays them by recognition of hydrophobic sites of some peptide species crucial for triggering amyloid formation. Hsp60 reduces the initial chaotic heterogeneity of A beta(1-42) sample at high concentration regimes. The understanding of chaperone action in counteracting pathological aggregation could be a starting point for potential new therapeutic strategies against neurodegenerative diseases.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available