http://content.iospress.com/articles/journal-of-alzheimers-disease/jad122113
Article type: Research Article
Affiliations: Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA, USA
Note: []
Correspondence to: Donald J. Graves, Department of Molecular, Cellular
and Developmental Biology, University of California, Santa Barbara, CA
93106, USA. Tel.: +1 805 893 5337; Fax: +1 805 893 5337; E-mail:
djgraves5@yahoo.com
Abstract: Abnormal
modifications in tau such as hyperphosphorylation, oxidation, and
glycation interfere with its interaction with microtubules leading to
its dissociation and self-aggregation into neurofibrillary tangles, a
hallmark of Alzheimer's disease (AD). Previously we reported that an
aqueous extract
of cinnamon has the ability to inhibit tau aggregation in vitro and can
even induce dissociation of tangles isolated from AD brain. In the
present study, we carried out investigations with cinnamaldehyde (CA)
and epicatechin (EC), two components of active cinnamon extract. We
found that CA and the oxidized form of EC (ECox) inhibited tau
aggregation in vitro and the activity was due to their interaction with
the two cysteine residues in tau. Mass spectrometry of a synthetic
peptide, SKCGS, representing the actual tau sequence, identified the
thiol as reacting with CA and ECox. Use of a cysteine double mutant of
tau showed the necessity of cysteine for aggregation inhibition by CA.
The interaction of CA with tau cysteines was reversible and the presence
of CA did not impair the biological function of tau in tubulin assembly
in vitro. Further, these compounds protected tau from oxidation caused
by the reactive oxygen species, H2O2, and prevented subsequent formation
of high molecular weight species that are considered to stimulate
tangle formation. Finally, we observed that EC can sequester highly
reactive and toxic byproducts of oxidation such as acrolein. Our results
suggest that small molecules that form a reversible interaction with
cysteines have the potential to protect tau from abnormal modifications.
Keywords: Aggregation, Alzheimer's disease, cinnamaldehyde, cysteine, epicatechin, hydrogen peroxide, reactive oxygen species, tau protein
DOI: 10.3233/JAD-122113
Journal: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 21-40, 2013
Accepted 1 March 2013
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Published: 2013
Price: EUR 27.50
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