Human Prefoldin Inhibits Amyloid-尾 (A尾) Fibrillation and Contributes to Formation of Nontoxic A尾 Aggregates

详细信息    查看全文

• 作者：Karin Margareta S枚rgjerd ; Tamotsu Zako ; Masafumi Sakono ; Peter C. Stirling ; Michel R. Leroux ; Takashi Saito ; Per Nilsson ; Misaki Sekimoto ; Takaomi C. Saido ; Mizuo Maeda
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：May 21, 2013
• 年：2013
• 卷：52
• 期：20
• 页码：3532-3542
• 全文大小：461K
• 年卷期：v.52,no.20(May 21, 2013)
• ISSN：1520-4995

文摘

Amyloid-尾 (A尾) peptides represent key players in the pathogenesis of Alzheimer鈥檚 disease (AD), and mounting evidence indicates that soluble A尾 oligomers mediate the toxicity. Prefoldin (PFD) is a molecular chaperone that prevents aggregation of misfolded proteins. Here we investigated the role of PFD in A尾 aggregation. First, we demonstrated that PFD is expressed in mouse brain by Western blotting and immunohistochemistry and found that PFD is upregulated in AD model APP23 transgenic mice. Then we investigated the effect of recombinant human PFD (hPFD) on A尾(1鈥?2) aggregation in vitro and found that hPFD inhibited A尾 fibrillation and induced formation of soluble A尾 oligomers. Interestingly, cell viability measurements using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that A尾 oligomers formed by hPFD were 30鈥?0% less toxic to cultured rat pheochromocytoma (PC12) cells or primary cortical neurons from embryonic C57BL/6CrSlc mice than previously reported A尾 oligomers (formed by archaeal PFD) and A尾 fibrils (p < 0.001). Thioflavin T measurements and immunoblotting indicated different structural properties for the different A尾 oligomers. Our findings show a relation between cytotoxicity of A尾 oligomers and structure and suggest a possible protective role of PFD in AD.