Formation of non-toxic Aβ fibrils by small heat shock protein under heat-stress conditions

• Published in: Biochemical and biophysical research communications 2013-01, Vol.430 (4), p.1259-1264
• Main Authors: Sakono, Masafumi, Utsumi, Arata, Zako, Tamotsu, Abe, Tetsuya, Yohda, Masafumi, Maeda, Mizuo
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Alzheimer's disease; Amyloid; Amyloid - chemistry; Amyloid - metabolism; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid-β; Animals; Cytotoxicity; DIMERS; DISSOCIATION; HEAT STRESS; HEAT-SHOCK PROTEINS; Heat-Shock Proteins - chemistry; Heat-Shock Proteins - metabolism; Heat-Shock Proteins, Small - chemistry; Heat-Shock Proteins, Small - metabolism; Heat-Shock Response; Hot Temperature; Humans; IN VITRO; Models, Chemical; Molecular chaperone; NERVOUS SYSTEM DISEASES; PATIENTS; PC12 Cells; PEPTIDES; Protein Structure, Tertiary; Rats; Schizosaccharomyces pombe; Schizosaccharomyces pombe Proteins - chemistry; Schizosaccharomyces pombe Proteins - metabolism; Small heat shock protein (sHsp); TEMPERATURE DEPENDENCE; TOXICITY; YEASTS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2012.12.059

► We examined effect of the quaternary structure of yeast sHsp on Aβ aggregation. ► Aβ aggregation was inhibited by the oligomeric form of sHsp, but not by dimeric sHsp. ► The fibrillar amyloids consisted of both Aβ and dimeric sHsp. ► They exhibited different inner structure and cytotoxicity from authentic Aβ amyloids. ► These results suggest the formation of new type fibrillar Aβ amyloid by sHsp. Small heat shock protein (sHsp) is a molecular chaperone with a conserved alpha-crystallin domain that can prevent protein aggregation. It has been shown that sHsps exist as oligomers (12–40mer) and their dissociation into small dimers or oligomers is functionally important. Since several sHsps are upregulated and co-localized with amyloid-β (Aβ) in senile plaques of patients with Alzheimer’s disease (AD), sHsps are thought to be involved in AD. Previous studies have also shown that sHsp can prevent Aβ aggregation in vitro. However, it remains unclear how the quaternary structure of sHsp influences Aβ aggregation. In this study, we report for the first time the effect of the quaternary structure of sHsp on Aβ aggregation using sHsp from the fission yeast Schizosaccharomyces pombe (SpHsp16.0) showing a clear temperature-dependent structural transition between an oligomer (30°C) and dimer (50°C) state. Aβ aggregation was inhibited by the oligomeric form of SpHsp16.0. In contrast, amyloid fibrils were formed in the presence of dimeric SpHsp16.0. Interestingly, these amyloid fibrils consisted of both Aβ and SpHsp16.0 and showed a low ThT intensity and low cytotoxicity due to their low binding affinity to the cell surface. These results suggest the formation of novel fibrillar Aβ amyloid with different characteristics from that of the authentic Aβ amyloid fibrils formed in the absence of sHsp. Our results also suggest the potential protective role of sHsp in AD under stress conditions.