Reduction of iron‐regulated amyloid precursor protein and β‐amyloid peptide by (–)‐epigallocatechin‐3‐gallate in cell cultures: implications for iron chelation in Alzheimer's disease

• Published in: Journal of neurochemistry 2006-04, Vol.97 (2), p.527-536
• Main Authors: Reznichenko, L., Amit, T., Zheng, H., Avramovich‐Tirosh, Y., Youdim, M. B. H., Mandel, S.
• Format: Article
• Language: English
• Subjects: (–)‐epigallocatechin‐3‐gallate; 5' Untranslated Regions; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Antigens, CD - metabolism; beta -Amyloid; Biological and medical sciences; Blotting, Western - methods; Brain; Catechin - analogs & derivatives; Catechin - pharmacology; Cell culture; Cell Line, Tumor; Chelating agents; Chelation; CHO Cells; Chromium; Cricetinae; Cricetulus; Deferoxamine; Deferoxamine - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose-Response Relationship, Drug; Drug Interactions; Electrophoresis, Gel, Two-Dimensional - methods; Gene Expression - drug effects; green tea; Humans; hypoxia; Immunoprecipitation - methods; Iron; Iron - physiology; Iron Chelating Agents - pharmacology; Medical sciences; Neuroblastoma; Neuroblastoma cells; neurodegeneration; Neurodegenerative diseases; Neurology; neuroprotection; Neuroprotective Agents - pharmacology; Post-transcription; Receptors, Transferrin - metabolism; Reporter gene; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transfection - methods; Transferrin receptors; Translation; Tumors of the nervous system. Phacomatoses; two‐dimensional gel electrophoresis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.03770.x

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 µm) 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 Fe2SO4 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 β‐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.