Therapeutics that target soluble oligomeric forms of Aβ and associated neurotoxicity have become a primary focus in recent years. In this issue of PNAS, Erich Wanker and colleagues show that EGCG, the main polyphenolic constituent of green tea, reduces cellular toxicity by inhibiting β amyloid and α-synuclein fibrillogenesis. These findings not only further support this group’s previous observation that EGCG redirects amyloidogenic polypeptides into loosely assembled non-toxic forms (Ehrnhoefer et al., 2008), but when taken together with our prior work, suggest that EGCG has multiple anti-amyloidogenic effects. Specifically, we previously demonstrated that Aβ-overproducing Tg2576 transgenic mice treated with EGCG displayed decreased cerebral Aβ levels/plaques, which required activity of the probable α-secretase ADAM10 (Rezai-Zadeh et al., 2005; Obregon, et al., 2006). The current findings from Wanker’s group dovetail well with our recent report that EGCG-treatment also improves spatial working memory deficits in Tg2576 mice (Rezai-Zadeh et al., 2008), raising the possibility that...  Read more

Therapeutics that target soluble oligomeric forms of Aβ and associated neurotoxicity have become a primary focus in recent years. In this issue of PNAS, Erich Wanker and colleagues show that EGCG, the main polyphenolic constituent of green tea, reduces cellular toxicity by inhibiting β amyloid and α-synuclein fibrillogenesis. These findings not only further support this group’s previous observation that EGCG redirects amyloidogenic polypeptides into loosely assembled non-toxic forms (Ehrnhoefer et al., 2008), but when taken together with our prior work, suggest that EGCG has multiple anti-amyloidogenic effects. Specifically, we previously demonstrated that Aβ-overproducing Tg2576 transgenic mice treated with EGCG displayed decreased cerebral Aβ levels/plaques, which required activity of the probable α-secretase ADAM10 (Rezai-Zadeh et al., 2005; Obregon, et al., 2006). The current findings from Wanker’s group dovetail well with our recent report that EGCG-treatment also improves spatial working memory deficits in Tg2576 mice (Rezai-Zadeh et al., 2008), raising the possibility that the compound mitigates against the neurotoxic effects of Aβ oligomers in vivo as well. It would be very interesting to specifically examine oligomeric Aβ species following EGCG treatment of Tg2576 mice.

Interestingly, the authors show that in their cell-free system, gallate moiety-containing green tea components ECG, GCG, and EGCG are more potently anti-fibrillogenic than tea polyphenols that lack the gallate moiety. These results suggest that the gallate moiety is necessary for amyloid remodeling in this scenario. These findings, too, are in accord with our most recent in vitro work where we discovered activities of various green tea constituents and related polyphenolic compounds. Specifically, we also found that the gallate moiety was key for EGCG’s ADAM10-dependent anti-amyloid activity. When considering that EGCG modulates both APP processing and aggregation, it is interesting to speculate on possible mechanistic overlap wherein oligomeric forms of Aβ, especially those found within neurons, may directly or indirectly impact APP processing. Regardless of the mechanism, bioavailability issues including circulating half-life and effective CNS concentration remain important, but surmountable, challenges for EGCG-based therapy. Despite these challenges, Wanker and colleagues’ findings demonstrate the high therapeutic potential for the prophylactic use of EGCG and related compounds against AD, PD, and perhaps other neurodegenerative disorders.

References:
1. Rezai-Zadeh K, Shytle D, Mori T, Hou H, Ehrhart J, Zeng J, Hardy J, Morgan D, Town T and Tan J. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer’s transgenic mice. J Neurosci. 2005 Sep 21;25(38):8807-14. Abstract

2. Obregon D, Rezai-Zadeh K, Zeng J, Shytle D, Town T and Tan J. ADAM10 activation is required for green tea EGCG-induced alpha-secretase cleavage of amyloid precursor protein. J Biol Chem. 2006 Jun 16;281(24):16419-27. Abstract

3. Rezai-Zadeh K, Arendash G, Fernandez F, Shytle D and Tan J. Green tea EGCG reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res. 2008 Jun 12;1214:177-87. Abstract

4. Ehrnhoefer DE, Bieschke J, Boeddrich A, Herbst M, Masino L, Lurz R, Engemann S, Pastore A, Wanker EE. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol. 2008 Jun;15(6):558-66. Abstract

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View all comments by Terrence Town

To date, green tea is generally regarded as safe by the U.S. Food and Drug Administration (FDA) (Wu and Wei, 2002) and has attracted attention for its health benefits, particularly with respect to its potential for preventing and treating cancer, cardiovascular diseases, inflammatory diseases, aging and neurodegenerative diseases, such as Parkinson and Alzheimer disease (PD and AD, respectively). Albeit the uncertainty on the capacity of green tea catechins to penetrate the brain, green tea was suggested to inversely correlate with the incidence of brain aging, dementia, and neurodegeneration. Yet in AD, no case-control study has been accomplished that points to a beneficial effect associated with green tea catechins consumption. A recent clinical efficacy study (sponsored by Charite University, Berlin, Germany) aims to evaluate whether the major component of green tea, (-)-epigallocatechin-3-gallate (EGCG), given daily as an oral medication over a period of 12 months, has a positive influence on the course of AD in patients in the early stage of the disease (estimated study...  Read more

To date, green tea is generally regarded as safe by the U.S. Food and Drug Administration (FDA) (Wu and Wei, 2002) and has attracted attention for its health benefits, particularly with respect to its potential for preventing and treating cancer, cardiovascular diseases, inflammatory diseases, aging and neurodegenerative diseases, such as Parkinson and Alzheimer disease (PD and AD, respectively). Albeit the uncertainty on the capacity of green tea catechins to penetrate the brain, green tea was suggested to inversely correlate with the incidence of brain aging, dementia, and neurodegeneration. Yet in AD, no case-control study has been accomplished that points to a beneficial effect associated with green tea catechins consumption. A recent clinical efficacy study (sponsored by Charite University, Berlin, Germany) aims to evaluate whether the major component of green tea, (-)-epigallocatechin-3-gallate (EGCG), given daily as an oral medication over a period of 12 months, has a positive influence on the course of AD in patients in the early stage of the disease (estimated study completion date is April 2011; U.S. FDA resources).

While evidence from AD epidemiological studies is limited, there are accumulating in vitro and animal preclinical studies demonstrating that EGCG can prevent amyloid-β peptide (Aβ)-induced neurotoxicity (Choi et al., 2001; Levites et al., 2003, Rezai-Zadeh et al., 2008; Reznichenko et al., 2006).

Supporting these observations, Erich Wanker and colleagues show in the current report in PNAS that EGCG reduces cellular toxicity of α-synuclein and Aβ fibrils by direct binding to their β-sheet-rich amyloid structures, thus mediating conformational changes to monomers or small diffusible oligomers. In addition, structure-activity relationship experiments with EGCG-related polyphenols suggest that the gallate moiety is crucial for the amyloid remodeling process. These observations might explain, for the first time, the neuroprotective activity of EGCG, as well as its effects in promoting the generation of soluble amyloid precursor proteins (APP) α and reducing Aβ levels and plaques in cell cultures and transgenic mouse models of AD. The vision of neuroscientists is to translate the preclinical and clinical findings of green tea catechins into a lifestyle arena. Indeed, this study emphasizes the necessity and importance of well-established human controlled studies to assess a risk reduction of AD in consumers of green tea catechins.

References:
Choi YT, Jung CH, Lee SR, Bae JH, Baek WK, Suh MH, Park J, Park CW, Suh SI (2001) The green tea polyphenol (-)-epigallocatechin gallate attenuates beta- amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci 70:603-614. Abstract

Levites Y, Amit T, Mandel S, Youdim MBH (2003) Neuroprotection and Neurorescue Against Amyloid beta Toxicity and PKC-Dependent Release of Non-Amyloidogenic Soluble Precusor Protein by Green Tea Polyphenol (-)-Epigallocatechin-3-gallate. FASEB J 17:952-954. Abstract

Rezai-Zadeh K, Arendash GW, Hou H, Fernandez F, Jensen M, Runfeldt M, Shytle RD, Tan J (2008) Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res 1214:177-187. Abstract

Reznichenko L, Amit T, Zheng H, Avramovich-Tirosh Y, Youdim MB, Weinreb O, Mandel S (2006) 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. J Neurochem 97:527-536. Abstract

Wu CD, Wei GX (2002) Tea as a functional food for oral health. Nutrition 18:443-444. Abstract

View all comments by Orly Weinreb