Hsp60, amateur chaperone in amyloid-beta fibrillogenesis

• Published in: Biochimica et biophysica acta Vol. 1860; no. 11; pp. 2474 - 2483
• Main Authors: Mangione, Maria Rosalia, Vilasi, Silvia, Marino, Claudia, Librizzi, Fabio, Canale, Claudio, Spigolon, Dario, Bucchieri, Fabio, Fucarino, Alberto, Passantino, Rosa, Cappello, Francesco, Bulone, Donatella, San Biagio, Pier Luigi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2016
• Subjects: Alzheimer disease; Alzheimer's disease treatment; amyloid; Amyloid - chemistry; Amyloid - metabolism; Amyloid aggregation; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Chaperonin; Chaperonin 60 - chemistry; Chaperonin 60 - metabolism; chaperonins; circular dichroism spectroscopy; fluorescence; gel chromatography; Humans; in vitro studies; in vivo studies; Inhibition mechanisms; Molecular chaperones; neurodegenerative diseases; Protein Binding; seeds; transmission electron microscopy; transport proteins; SEC; Chaperonin; CD; ThT; AD; HSP; Molecular chaperones; Amyloid aggregation; AFM; EM; Alzheimer's disease treatment; Inhibition mechanisms
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.07.019

Molecular chaperones are a very special class of proteins that play essential roles in many cellular processes like folding, targeting and transport of proteins. Moreover, recent evidence indicates that chaperones can act as potentially strong suppressor agents in Alzheimer's disease (AD). Indeed, in vitro experiments demonstrate that several chaperones are able to significantly slow down or suppress aggregation of Aβ peptide and in vivo studies reveal that treatment with specific chaperones or their overexpression can ameliorate some distinct pathological signs characterizing AD. Here we investigate using a biophysical approach (fluorescence, circular dichroism (CD), transmission electron (TEM) and atomic force (AFM) microscopy, size exclusion chromatography (SEC)) the effect of the human chaperonin Hsp60 on Aβ fibrillogenesis. We found that Hsp60 powerfully inhibits Aβ amyloid aggregation, by closing molecular pathways leading to peptide fibrillogenesis. We observe that Hsp60 inhibits Aβ aggregation through a more complex mechanism than a simple folding chaperone action. The action is specifically directed toward the early oligomeric species behaving as aggregation seeds for on-pathway amyloid fibrillogenesis. Understanding the specificity of the molecular interactions of Hsp60 with amyloid Aβ peptide allowed us to emphasize the important aspects to be taken into consideration when considering the recent promising therapeutic strategies for neurodegeneration [Display omitted] •The human chaperonin Hsp60 effect on Aβ amyloid peptide aggregation is studied.•Aβ amyloid aggregation is inhibited in the presence of Hsp60.•Hsp60 selectively acts on the species acting as seeds for fibrillogenesis.•Once active seeds are recruited from Hsp60, Aβ peptide is unable to fibrillate.•Our study contributes to basic knowledge for chaperones-based AD therapies.