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The Journal of Neuroscience, September 21, 2005, 25(38):8807-8814; doi:10.1523/JNEUROSCI.1521-05.2005

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Neurobiology of Disease
Green Tea Epigallocatechin-3-Gallate (EGCG) Modulates Amyloid Precursor Protein Cleavage and Reduces Cerebral Amyloidosis in Alzheimer Transgenic Mice

Kavon Rezai-Zadeh,^1 * Doug Shytle,^1,2 * Nan Sun,^1 * Takashi Mori,^1,4 Huayan Hou,¹ Deborah Jeanniton,¹ Jared Ehrhart,¹ Kirk Townsend,¹ Jin Zeng,¹ David Morgan,³ John Hardy,⁵ Terrence Town,^1,6 and Jun Tan^1,2

¹Neuroimmunology Laboratory, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, ²Center for Excellence in Aging and Brain Repair, Department of Neurosurgery, ³Alzheimer's Disease Research Laboratory, Department of Pharmacology, University of South Florida, Tampa, Florida 33613, ⁴Institute of Medical Science, Saitama Medical School, Saitama 350-8550, Japan, ⁵Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, and ⁶Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of -amyloid (A) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces A generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APP_sw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the -C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-. These cleavage events are associated with elevated -secretase activity and enhanced hydrolysis of tumor necrosis factor -converting enzyme, a primary candidate -secretase. As a validation of these findings in vivo, we treated Tg APP_sw transgenic mice overproducing A with EGCG and found decreased A levels and plaques associated with promotion of the nonamyloidogenic -secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.

Key words: aging; Alzheimer's disease; -amyloid; green tea; PKC; protease

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Received April 18, 2005; revised August 8, 2005; accepted August 10, 2005.

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