Aβ (amyloid β-peptide) is believed to cause AD (Alzheimer's disease). Aβ42 (Aβ comprising 42 amino acids) is substantially more neurotoxic than Aβ40 (Aβ comprising 40 amino acids), and this increased toxicity correlates with the existence of unique Aβ42 oligomers. Met35 oxidation to sulfoxide or sulfone eliminates the differences in early oligomerization between Aβ40 and Aβ42. Met35 oxidation to sulfoxide has been reported to decrease Aβ assembly kinetics and neurotoxicity, whereas oxidation to sulfone has rarely been studied. Based on these data, we expected that oxidation of Aβ to sulfone would also decrease its toxicity and assembly kinetics. To test this hypothesis, we compared systematically the effect of the wild-type, sulfoxide and sulfone forms of Aβ40 and Aβ42 on neuronal viability, dendritic spine morphology and macroscopic Ca2+ currents in primary neurons, and correlated the data with assembly kinetics. Surprisingly, we found that, in contrast with Aβ-sulfoxide, Aβ-sulfone was as toxic and aggregated as fast, as wild-type Aβ. Thus, although Aβ-sulfone is similar to Aβ-sulfoxide in its dipole moment and oligomer size distribution, it behaves similarly to wild-type Aβ in its aggregation kinetics and neurotoxicity. These surprising data decouple the toxicity of oxidized Aβ from its initial oligomerization, and suggest that our current understanding of the effect of methionine oxidation in Aβ is limited.
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Research Article|
December 22 2010
Surprising toxicity and assembly behaviour of amyloid β-protein oxidized to sulfone
Panchanan Maiti;
Panchanan Maiti
*Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, 635 Charles E. Young Drive South, Los Angeles, CA 90025, U.S.A.
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Roberto Piacentini;
Roberto Piacentini
†Institute of Human Physiology, Catholic University Medical School, Largo F. Vito 1, Rome 00168, Italy
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Cristian Ripoli;
Cristian Ripoli
†Institute of Human Physiology, Catholic University Medical School, Largo F. Vito 1, Rome 00168, Italy
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Claudio Grassi;
Claudio Grassi
†Institute of Human Physiology, Catholic University Medical School, Largo F. Vito 1, Rome 00168, Italy
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Gal Bitan
Gal Bitan
1
*Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, 635 Charles E. Young Drive South, Los Angeles, CA 90025, U.S.A.
‡Brain Research Institute, University of California at Los Angeles, 635 Charles E. Young Drive South, Los Angeles, CA 90025, U.S.A.
§Molecular Biology Institute, University of California at Los Angeles, 635 Charles E. Young Drive South, Los Angeles, CA 90025, U.S.A.
1To whom correspondence should be addressed (email gbitan@mednet.ucla.edu).
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Publisher: Portland Press Ltd
Received:
August 30 2010
Revision Received:
October 18 2010
Accepted:
November 02 2010
Accepted Manuscript online:
November 02 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 433 (2): 323–332.
Article history
Received:
August 30 2010
Revision Received:
October 18 2010
Accepted:
November 02 2010
Accepted Manuscript online:
November 02 2010
Connected Content
A correction has been published:
Correction: Surprising toxicity and assembly behaviour of amyloid β-protein oxidized to sulfone
Citation
Panchanan Maiti, Roberto Piacentini, Cristian Ripoli, Claudio Grassi, Gal Bitan; Surprising toxicity and assembly behaviour of amyloid β-protein oxidized to sulfone. Biochem J 15 January 2011; 433 (2): 323–332. doi: https://doi.org/10.1042/BJ20101391
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