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Int. J. Mol. Sci. 2012, 13(5), 5324-5337; doi:10.3390/ijms13055324

Aβ-40 Y10F Increases βfibrils Formation but Attenuates the Neurotoxicity of Amyloid-β Peptide

1,*  and 2,*
1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing 100191, China 2 Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing 100191, China 3 College of Life Science, Capital Normal University, Beijing 100048, China
* Authors to whom correspondence should be addressed.
Received: 11 March 2012 / Revised: 11 April 2012 / Accepted: 23 April 2012 / Published: 25 April 2012
(This article belongs to the Special Issue Molecular Mechanisms of Organ-Specific Toxicity)
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Alzheimer’s disease (AD) is characterized by the abnormal aggregation of amyloid-β peptide (Aβ) in extracellular deposits known as senile plaques. The tyrosine residue (Tyr-10) is believed to be important in Aβ-induced neurotoxicity due to the formation of tyrosyl radicals. To reduce the likelihood of cross-linking, here we designed an Aβ-40 analogue (Aβ-40 Y10F) in which the tyrosine residue was substituted by a structurally similar residue, phenylalanine. The aggregation rate was determined by the Thioflavin T (ThT) assay, in which Aβ-40 Y10F populated an ensemble of folded conformations much quicker and stronger than the wild type Aβ. Biophysical tests subsequently confirmed the results of the ThT assay, suggesting the measured increase of β-aggregation may arise predominantly from enhancement of hydrophobicity upon substitution and thus the propensity of intrinsic β-sheet formation. Nevertheless, Aβ-40 Y10F exhibited remarkably decreased neurotoxicity compared to Aβ-40 which could be partly due to the reduced generation of hydrogen peroxide. These findings may lead to further understanding of the structural perturbation of Aβ to its fibrillation.
Keywords: Alzheimer’s disease; amyloid-β peptide; βfibrils; neurotoxicity Alzheimer’s disease; amyloid-β peptide; βfibrils; neurotoxicity
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dai, X.; Chang, P.; Liu, W.; Xu, K.; Sun, Y.; Zhu, S.; Jiang, Z. Aβ-40 Y10F Increases βfibrils Formation but Attenuates the Neurotoxicity of Amyloid-β Peptide. Int. J. Mol. Sci. 2012, 13, 5324-5337.

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