Free Radic Biol Med. 2007 Aug 15;43(4):546-56. Epub 2007 May 16. Links
A novel approach of proteomics and transcriptomics to study the
mechanism of action of the antioxidant-iron chelator green tea
polyphenol (-)-epigallocatechin-3-gallate.
Weinreb O, Amit T, Youdim MB.
Eve Topf and USA National Parkinson Foundation Centers of Excellence
for Neurodegenerative Diseases Research and Department of
Pharmacology, Rappaport Family Research Institute, Technion-Faculty of
Medicine, Haifa 31096, Israel.

Previous findings suggest that the antioxidant-iron chelator green tea
polyphenol (-)-epigallocatechin-3-gallate (EGCG) may have a
neurorescue impact in aging and neurodegenerative diseases to retard
or even reverse the accelerated rate of neuronal degeneration. The
present study sought a deeper elucidation of the molecular neurorescue
activity of EGCG in a progressive neurotoxic model of long-term serum
deprivation of human SH-SY5Y neuroblastoma cells. In this model,
proteomic analysis revealed that EGCG (0.1-1 muM) affected the
expression levels of diverse proteins, including proteins related to
cytoskeletal components, metabolism, heat shock, and binding. EGCG
induced the levels of cytoskeletal proteins, such as beta tubulin IV
and tropomyosin 3, playing a role in facilitating cell assembly. In
accordance, EGCG increased the levels of the binding protein 14-3-3
gamma, involved in cytoskeletal regulation and signal transduction
pathways in neurons. Additionally, EGCG decreased protein levels and
mRNA expression of the beta subunit of the enzyme prolyl 4-
hydroxylase, which belongs to a family of iron-oxygen sensors of
hypoxia-inducible factor (HIF) prolyl hydroxylases that negatively
regulate the stability and degradation of several proteins involved in
cell survival and differentiation. Accordingly, EGCG decreased protein
levels of two molecular chaperones that were associated with HIF
regulation, the immunoglobulin-heavy-chain binding protein and the
heat shock protein 90 beta. Thus, the present study sheds some light
on the antioxidative-iron chelating activities of EGCG underlying its
neuroprotective/neurorescue mechanism of action, further suggesting a
potential neurodegenerative-modifying effect for EGCG.

PMID: 17640565 [PubMed - in process]
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J Neurochem. 2006 Apr;97(2):527-36. Epub 2006 Mar 15. Links
Reduction of iron-regulated amyloid precursor protein and beta-amyloid
peptide by (-)-epigallocatechin-3-gallate in cell cultures:
implications for iron chelation in Alzheimer's disease.Reznichenko L,
Amit T, Zheng H, Avramovich-Tirosh Y, Youdim MB, Weinreb O, Mandel S.
Eve Topf and US National Parkinson Foundation Centers for
Neurodegenerative diseases and Department of Pharmacology, Faculty of
Medicine, Technion, Haifa, Israel.

Brain iron dysregulation and its association with amyloid precursor
protein (APP) plaque formation are implicated in Alzheimer's disease
(AD) pathology and so iron chelation could be considered a rational
therapeutic strategy for AD. Here we analyzed the effect of the main
polyphenol constituent of green tea, (-)-epigallocatechin-3-gallate
(EGCG), which possesses metal-chelating and radical-scavenging
properties, on the regulation of the iron metabolism-related proteins
APP and transferrin receptor (TfR). EGCG exhibited potent iron-
chelating activity comparable to that of the prototype iron chelator
desferrioxamine, and dose dependently (1-10 microm) increased TfR
protein and mRNA levels in human SH-SY5Y neuroblastoma cells. Both the
immature and full-length cellular holo-APP were significantly reduced
by EGCG, as shown by two-dimensional gel electrophoresis, without
altering APP mRNA levels, suggesting a post-transcriptional action.
Indeed, EGCG suppressed the translation of a luciferase reporter gene
fused to the APP mRNA 5'-untranslated region, encompassing the APP
iron-responsive element. The finding that Fe(2)SO(4) reversed the
action of EGCG on APP and TfR proteins reinforces the likelihood that
these effects are mediated through modulation of the intracellular
iron pool. Furthermore, EGCG reduced toxic beta-amyloid peptide
generation in Chinese hamster ovary cells overexpressing the APP
'Swedish' mutation. Thus, the natural non-toxic brain-permeable EGCG
may provide a potential therapeutic approach for AD and other iron-
associated disorders.

PMID: 16539659 [PubMed - indexed for MEDLINE]
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