Characterization of Early Stage Intermediates in the Nucleation Phase of A尾 Aggregation

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• 作者：Jiali Zhai ; Tzong-Hsien Lee ; David H. Small ; Marie-Isabel Aguilar
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：February 14, 2012
• 年：2012
• 卷：51
• 期：6
• 页码：1070-1078
• 全文大小：388K
• 年卷期：v.51,no.6(February 14, 2012)
• ISSN：1520-4995

文摘

Alzheimer鈥檚 disease (AD) is a common form of dementia, which is characterized by the presence of extracellular amyloid plaques comprising the amyloid 尾 peptide (A尾). Although the mechanism underlying AD pathogenesis remains elusive, accumulating evidence suggests that the process of amyloid fibril formation is a surface-mediated event, which plays an important role in AD onset and progression. In this study, the mechanism of A尾 aggregation on hydrophobic surfaces was investigated with dual polarization interferometry (DPI), which provides real-time information on early stages of the aggregation process. Aggregation was monitored on a hydrophobic C18 surface and a polar silicon oxynitride surface. The DPI results showed a characteristic A尾 aggregation pattern involving a decrease in the density of A尾 at the surface followed by an increase in the thickness on the hydrophobic C18 chip. Most importantly, the DPI measurements provided unique information on the early stages of A尾 aggregation, which is characterized by the presence of initially slow nucleus formation process followed by exponential fibril elongation. The dimensions of the putative nucleus corresponded to a thickness of 5 nm for both A尾40 and A尾42, which may represent about 10鈥?5 molecules. The results thus support the nucleation-dependent polymerization model as indicated by the presence of a nucleation phase followed by an exponential growth phase. These results are the first reported measurements of the real-time changes in A尾 molecular structure during the early stages of amyloid formation at the nanometer level.