Characterization of early stage intermediates in the nucleation phase of A {Beta} aggregation

Jiali Zhai, Tzong-Hsien Lee, David Small, Marie Aguilar

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20 Citations (Scopus)

Abstract

Alzheimer s disease (AD) is a common form of dementia, which is characterized by the presence of extracellular amyloid plaques comprising the amyloid beta peptide (Abeta). 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 Abeta 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 Abeta aggregation pattern involving a decrease in the density of Abeta 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 Abeta 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 approximately 5 nm for both Abeta40 and Abeta42, which may represent about 10-15 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 Abeta molecular structure during the early stages of amyloid formation at the nanometer level.
Original languageEnglish
Pages (from-to)1070 - 1078
Number of pages9
JournalBiochemistry
Volume51
Issue number6
DOIs
Publication statusPublished - 2012

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