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Characterization of early stage intermediates in the nucleation phase of Aβ aggregation

Citation

Zhai, J and Lee, TH and Small, DH and Aguilar, M-I, Characterization of early stage intermediates in the nucleation phase of Aβ aggregation, Biochemistry, 51, (6) pp. 1070-1078. ISSN 0006-2960 (2012) [Refereed Article]

Copyright Statement

Copyright 2012 American Chemical Society

DOI: doi:10.1021/bi201871r

Abstract

Alzheimer's disease (AD) is a common form of dementia, which is characterized by the presence of extracellular amyloid plaques comprising the amyloid β peptide (Aβ). 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 Aβ 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 Aβ aggregation pattern involving a decrease in the density of Aβ 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 Aβ 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 Aβ40 and Aβ42, 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 Aβ molecular structure during the early stages of amyloid formation at the nanometer level.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Neurodegenerative Disorders Related to Ageing
Author:Small, DH (Professor David Small)
ID Code:80053
Year Published:2012
Web of Science® Times Cited:13
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-10-18
Last Modified:2013-05-07
Downloads:0

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