The Journal of Nutrition

Proceedings of the Fourth International Scientific Symposium on Tea and Human Health

Targeting Multiple Neurodegenerative Diseases
Etiologies with Multimodal-Acting Green
Tea Catechins

1,2

Silvia A. Mandel,* Tamar Amit, Limor Kalfon, Lydia Reznichenko, and Moussa B. H. Youdim

Eve Topf Center for Neurodegenerative Diseases Research and Department of Pharmacology, Faculty of Medicine, Technion,
Haifa, Israel

Abstract

Green tea is currently considered a source of dietary constituents endowed with biological and pharmacological activities

relevant to human health. Human epidemiological and new animal data suggest that the pharmacological benefits of tea

drinking may help to protect the brain as we age. Indeed, tea consumption is inversely correlated with the incidence

of dementia and Alzheimer’s and Parkinson’s diseases. In particular, its main catechin polyphenol constituent (2)-

epigallocatechin-3-gallate has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and

animal models of neurological disorders. The intense efforts dedicated in recent years to shed light on the molecular

mechanisms participating in the brain protective action of green tea indicate that in addition to the known antioxidant

activity of catechins, the modulation of signal transduction pathways, cell survival/death genes, and mitochondrial function

all contribute significantly to the induction of neuron viability. Because of the multietiological character of neurodegen-

erative disease pathology, these natural compounds are receiving significant attention as therapeutic cytoprotective

agents that simultaneously manipulate multiple desired targets in the central nervous system. This article elaborates on

the multimodal activities of green tea polyphenols with emphasis on their recently described neurorescue/neuro-

regenerative and mitochondrial stabilization actions.

J. Nutr. 138: 1578S–1583S, 2008.

Introduction

Despite the lack of well-controlled clinical trials with tea
polyphenols in neurodegenerative diseases, human epidemiolog-
ical and new animal data suggest that the pharmacological
benefits of tea drinking may help protect the brain as we age.
Indeed, tea consumption is inversely correlated with the incidence

of dementia, Alzheimer’s disease (AD),

3

and Parkinson’s disease

(PD), which may explain why there are significantly lower rates of
age-related neurological disorders among Asians than in Euro-
peans or Americans (1). In a cross-sectional study conducted in
Japan aimed at investigating the association between consump-
tion of green tea and cognitive function in elderly Japanese
subjects, it was found that consumption of 2 or more cups/d (100
mL/cup) of green tea is associated with lower prevalence of
cognitive impairment (2). In a case-control study in the United
States, it was found that people who consumed 2 cups/d or more
of tea presented a decreased risk of PD (3). In support of this
finding, a recent prospective cohort study of nearly 30,000
Finnish adults aged 25–74 y followed for 13 y found that drinking
3 or more cups (200 mL/cup) of tea is associated with a reduced
risk of PD (4). These findings emphasize the importance of well-
designed controlled studies to assess risk reduction for PD and AD
in consumers of green and black tea. The Michael J. Fox
Foundation has awarded a grant to the team of Piu Chan from
Xuanwu Hospital, Beijing, China, to carry out the first-ever

3

Abbreviations used: Ab, amyloid b-peptide; AD, Alzheimer’s disease; APP,

amyloid precursor protein; COMT, catechol-O-methyl transferase; DA, dopa-
mine; DAT, dopamine transporter; EGCG, (2)-epigallocatechin-3-gallate; ERK1/2,
extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase;
MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA, 6-hydroxydopa-
mine; OS, oxidation stress; PD, Parkinson’s disease; PKC, protein kinase C;
sAPPa, soluble amyloid precursor protein-a; SOD, superoxide dismutase.

1

Published in a supplement to The Journal of Nutrition. Presented at the

conference ‘‘Fourth International Scientific Symposium on Tea and Human
Health,’’ held in Washington, DC at the U.S. Department of Agriculture on
September 18, 2007. The conference was organized by the Tea Council of the
U.S.A. and was cosponsored by the American Cancer Society, the American
College of Nutrition, the American Medical Women’s Association, the American
Society for Nutrition, and the Linus Pauling Institute. Its contents are solely the
responsibility of the authors and do not necessarily represent the official views of
the Tea Council of the U.S.A. or the cosponsoring organizations. Supplement
coordinators for the supplement publication were Lenore Arab, University of
California, Los Angeles, CA and Jeffrey Blumberg, Tufts University, Boston, MA.
Supplement coordinator disclosure: L. Arab and J. Blumberg received honorar-
ium and travel support from the Tea Council of the U.S.A. for cochairing the
Fourth International Scientific Symposium on Tea and Human Health and for
editorial services provided for this supplement publication; they also serve as
members of the Scientific Advisory Panel of the Tea Council of the U.S.A.

2

Author disclosures: S. A. Mandel received travel support from the Tea Council

of the U.S.A. for speaking at the Fourth International Scientific Symposium on
Tea and Human Health and for preparing this manuscript for publication; T. Amit,
L. Kalfon, L. Reznichenko, and M. B. H. Youdim, no conflicts of interest.
* To whom correspondence should be addressed. E-mail: [e-mail].
ac.il.

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multicenter, double-blind, randomized, placebo-controlled study
to investigate the safety, tolerability, and potential neuroprotec-
tive effects of green tea polyphenols in patients with early PD.

Intense efforts have been dedicated during the past 5 y to shed

light on the molecular mechanisms and cell-signaling pathways
participating in the neuroprotective/neuroregenerative action
of green tea. The emerging data indicate that the antioxidant/
metal-chelating attributes of the catechin polyphenols are un-
likely to serve as the sole explanation for their neuroprotective
and neurorescue capacity. This article presents the state of the
art in the molecular mechanisms and cell-signaling pathways
implicated in the neuroprotective action of green tea catechins,
with emphasis on their recently described neurorescue effect and
mitochondrial stabilization potency.

Etiopathology of neurodegenerative diseases
Neurodegenerative disorders are progressive diseases of the
nervous system involving damage or loss of neurons in the brain
and/or spinal cord, which can occur at any time of life.
Neurodegeneration in PD or AD or other neurodegenerative
diseases, such as Huntington disease and amyotrophic lateral
sclerosis, appears to be multifactorial, where a complex set of
toxic reactions lead to the demise of neurons (5,6). Common
features involve impairment of protein handling and aggregation
associated with dysfunction of the ubiquitin-proteasome system,
depletion of endogenous antioxidants, reduced expression of
trophic factors, inflammation, glutamatergic excitotoxicity, ex-
pression of proapoptotic proteins, and increases of iron and
nitric oxide leading to oxidative-stress (OS) damage (7–9). An
unresolved question, however, is to determine which of these
factors constitute the primary event, the sequence in which they
act, and where the point of convergence is or the final pathway
by which the predisposed neuronal cell types die in the affected
brain areas. Because of the multietiological character of the
pathology, novel therapeutic neuroprotective strategies support
the idea that simultaneous manipulation of multiple desired
targets in the central nervous system will exert higher therapeu-
tic effectiveness (10,11). Thus, it is not surprising, that green tea
catechins have attracted increasing interest as therapeutic
cytoprotective agents for the treatment of neurological disorders
because of their broad spectrum of biological/pharmacological
activities, including cardiovascular, antiinflammatory, and anti-
carcinogenesis effects (12–14) and, more recently recognized,
antidiabetic (15,16), antiobesity (17), and neuroprotective/
neurorestorative properties (18).

Neuroprotection/neurorescue by green
tea polyphenols
There is a growing recognition that polyphenolic catechins exert
a protective role in neurodegeneration. The neuroprotective
effect has been long established in animal models of neurological
disorders: (2)-epigallocatechin-3-gallate (EGCG), the major
polyphenol component of green tea, has been shown to improve
age-related cognitive decline and to protect against cerebral
ischemia/reperfusion injuries (19,20) and brain inflammation
and neuronal damage in experimental autoimmune encephalo-
myelitis (21). Furthermore, the treatment of EGCG significantly
prolonged the symptom onset and life span and attenuated death
signals in a mouse amyotrophic lateral sclerosis model with the
human G93A-mutated Cu/Zn-superoxide dismutase (SOD)
gene (SOD1) (22). Similarly, a green tea polyphenol extract or
isolated EGCG prevented striatal dopamine (DA) depletion and
substantia nigra dopaminergic neuron loss when given chron-
ically to mice treated with the parkinsonism-inducing neuro-

toxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
(23). More recently, long-term administration of a preparate
of green tea catechins (polyphenol E) or EGCG has been dem-
onstrated to improve spatial cognition and learning ability in
rats (24) and to reduce cerebral amyloidosis in Alzheimer’s
transgenic mice, respectively (25).

In line with the in vivo findings, cell culture studies have

demonstrated that green tea catechins prevented neuronal cell
death caused by the neurotoxins 6-hydroxydopamine (6-OHDA),
1-methyl-4-phenylpyridinium and amyloid b-peptide (Ab) (26–
29). More recently, EGCG was reported to exert a neurorescue
activity in long-term serum-deprived rat pheochromocytoma
(PC12) cells and to promote neurite outgrowth (30). It remains
to be established whether there is any mechanistic relation
between survival and differentiation induced by EGCG and
also to what extent the in vitro findings could be replicated in
vivo. To test this assumption, we have examined the possible
neurorescue/neurorestorative activity in a post-MPTP-induced
nigrostriatal DA neurodegeneration model of PD in mice. MPTP
(20 mg/kg, i.p., per d) was administered for 4 d, followed by a
further 4-d resting period, and, at d 8, EGCG (5 mg/kg or water)
was administered orally, over a total treatment period of 22 d.
MPTP caused a significant reduction in viability of tyrosine-
hydroxylase-positive cells, whereas oral EGCG administration
post-MPTP resulted in a substantial recovery of the neurons.
Current experiments are in progress to determine effective doses
and duration of treatment. Thus, the neurorescue action of
EGCG may suggest a potential disease-modifying effect for the
drug, similar to what has been recently described for the novel
anti-Parkinson drug rasagiline (N-propargyl-1(R)-aminoindan),
a second-generation selective inhibitor of monoamine oxidase-B
(31).

Molecular mechanisms of neuroprotective/
neurorescue action of EGCG
The protein kinase C pathway.

Emerging evidence suggests

that the biological actions of green tea catechins relate not simply
to their antioxidant/radical-scavenging potential but also to the
modulation of various protein kinase signaling pathways. Our
recent in vitro cell-signaling studies on the neuroprotective
mechanistic action of EGCG revealed a specific involvement of
protein kinase C (PKC) (26,32), a family of serine/threonine
kinases consisting of 11 isoforms, which are divided into 3
subclasses: conventional (a, b

I

, b

II

, g), novel (d, e, u, h, m), and

atypical [i (mouse)/l (human), z] (33). PKC has a fundamental
role in the regulation of cell survival, programmed cell death,
long-term potentiation (34), and consolidation of different types
of memory (35,36). Indeed, it has been suggested that phar-
macological interventions aimed at modulating specific PKC
isozymes or PKC-mediated signal transduction pathways may
constitute a potential therapeutic tool for senescence or age-
related pathologies that are responsible for memory disturbances
(37). The induction of PKC activity in neurons is thought to be a
prerequisite for neuroprotection against several exogenous
insults. Indeed, PKCe activation after ischemic preconditioning
or pharmacological preconditioning (with either PKCe, NMDA,
or A1AR agonists) was shown to be essential for neuroprotection
against oxygen/glucose deprivation in organotypic slice cultures
(38). In accordance, activation of PKC by estrogen or by the grape
flavonoid resveratrol protected rat cortical or hippocampal
neurons against Ab toxicity, respectively (39,40).

PKC activation by EGCG prevents apoptosis and mito-

chondrial membrane potential collapse.

A rapid phosphor-

ylative activation of PKC by EGCG is thought to be the main

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mechanism accounting for its neuroprotective activity against
several neurotoxins such as Ab (28), serum withdrawal (30,41),
and 6-OHDA (26) and for its neurorescue effect against long-
term growth factor withdrawal (30). In addition, EGCG induced
a rapid translocation of the isoform PKCa to the membrane
compartment in response to EGCG in human astroglioma or rat
PC12 cells (30,42). This isozyme is particularly important in
neuronal growth and differentiation in the brain. These findings
are supported by animal studies showing that a 2-wk oral
consumption of EGCG prevented the extensive depletion of
PKCa isoform and counteracted the robust increase of Bax
protein in the striatum and the dopaminergic neurons of the
substantia nigra pars compacta of mice intoxicated with MPTP,
respectively (43).

Recently, we identified a novel pathway in the neuroprotective

mechanism of action of EGCG that involves a rapid PKC-
mediated degradation of the Bad protein by the ubiquitin-
proteasome system and a more pronounced reduction after 24 h
in cell culture (32). Bad may directly contribute to the opening of
the mitochondrial megachannel permeability transition pore by
its heterodimerization with the mitochondrial death suppressor
proteins Bcl-2 and/or BclxL, thus neutralizing their antiapoptotic
function (44). Indeed, we have recently found that the adminis-
tration of EGCG for 30 min prevented the dissipation of the
mitochondrial membrane potential, DCm, induced by short-term
(4 h) exposure to 6-OHDA (data not presented). This appears to
involve activation of the PKC signaling pathway because
pretreatment with the pharmacological general PKC inhibitor
GF109203X blunted the protective effect of EGCG on DCm.

PKC activation by EGCG is beneficial for AD and PD.

Neuronal amyloidosis in AD is characterized by extracellular
deposition of Ab peptide, derived from proteolytic cleavage of
amyloid precursor protein (APP), a type I integral membrane
protein. APP can be processed via alternative pathways: a
nonamyloidogenic secretory pathway includes cleavage of APP
to sAPPa by a putative a-secretase within the sequence of the
amyloidogenic Ab peptide, thus precluding the formation of Ab,
whereas the formation of Ab is regulated by the sequential
action of b- and g-secretases (45). Our pioneer studies have
demonstrated that either short- or long-term incubation with
EGCG promotes the generation of the nontoxic sAPPa via PKC-
dependent activation of a-secretase (28,46). New supportive
data came from a study conducted in an Alzheimer’s transgenic
mice model, showing that EGCG promotes sAPPa generation
through activation of a-secretase cleavage (25). This was ac-
companied by a significant reduction in cerebral Ab levels and
b

-amyloid plaques.

Another potential beneficial effect of PKC activation in AD is

related to the recent finding that neuronal overexpression of
PKCe in transgenic mice expressing familial AD mutant forms of
the human APP decreases Ab levels and plaque burden, and this
is accompanied by increased activity of endothelin-converting
enzyme, which degrades Ab (47). Because EGCG has been
shown to increase the levels of PKC isoforms a and e in mouse
hippocampus and striatum (28,43), it can be hypothesized that
in AD pathology, EGCG may reduce Ab levels, both via
concomitant stimulation of sAPPa secretion and promotion of
Ab clearance through increased endothelin-converting enzyme
activity.

In PD, a possible beneficial effect of green tea polyphenols

maybe related to the increased internalization of the DA
presynaptic transporters (DAT) by EGCG, eventually resulting
in a rise in the synaptic DA level. This effect was mimicked by
phorbol 12-myristate 13-acetate, a potent activator of PKC, and

abolished by blockade of the PKC pathway (48), suggestive of a
potential therapeutic target of PKC in the brain as a result of
green tea intake. This observation, together with the finding that
EGCG inhibited catechol-O-methyltransferase (COMT) activity
at a low IC50 concentration (0.2 mmol/L) in rat liver cytosol
homogenates (49), may be of particular significance for PD
patients given that DA and related catecholamines are physio-
logical substrates of COMT. Indeed, COMT inhibitors entaca-
pone and tolcapone, clinically prescribed to PD-affected
individuals, dose-dependently inhibit the formation of the major
metabolite of levodopa, 3-O-methyldopa, thereby improving its
bioavailability in the brain (50).

Other signaling pathways.

In addition to PKC, other cell-

signaling pathways have been implicated in the action of green
tea catechins, such as the mitogen-activated protein kinases
(MAPK), phosphatidylinositide 3#-OH kinase/AKT and protein
kinase A signaling cascades, and cell calcium influx regulation
[for review see Mandel et al. (18)]. These cascades have been
shown to play central functions in neuronal protection against a
variety of extracellular insults and to be essential for neuronal
differentiation and survival (51,52). In general, flavonoids can
activate MAPK signaling cascades in both neuronal and ex-
traneuronal tissues and neutralize the decline in the mitogen
and growth factor-induced extracellular signal-regulated kinase
(ERK1/2) activity caused by exogenous OS-inducing agents
(26,53). Low doses of (2)-epicatechin were recently shown to
stimulate phosphorylation of the cAMP-response element bind-
ing protein, a regulator of neuronal viability and synaptic
plasticity activity through both ERK1/2 and AKT in primary
cortical neurons (54). Using the same cell culture conditions, this
group of researchers demonstrated that activation/phosphorylation
of both kinases was also involved in the antiapoptotic action of
submicromolar concentrations of the flavanone hesperetin and
its metabolite, 5-nitro-hesperetin (55). A number of flavonoids
and phenolic antioxidants, at their respective low protective con-
centrations, were demonstrated to activate the expression of some
stress-response genes, such as the phase II drug-metabolizing
enzymes glutathione-S-transferase and heme-oxygenase-1, likely
via activation of the MAPK pathway (56). Although EGCG had
no effect on ERK1/2 phosphorylative levels in the absence of any
exogenous damage, it was able to counteract the decline in
ERK1/2 induced by 6-OHDA in neuroblastoma cells (26).

Antioxidant and iron chelating activity of green tea
polyphenols.

Tea catechins are powerful hydrogen-donating

antioxidants and free radical scavengers of reactive oxygen and
nitrogen species in in vitro systems (57–59). The neuroprotective
effect of green tea polyphenols may also involve the regulation of
antioxidant protective enzymes such as SOD and catalase in
mouse striatum (23). In peripheral tissue, it has been shown
that a number of flavonoids and phenolic antioxidants activate
the expression of some stress-response genes such as the phase II
drug metabolizing enzymes, glutathione-S-transferase and heme-
oxygenase-1 in correlation with an increase in the activity and
nuclear binding of the transcription factors Nrf1 and Nrf2 to the
antioxidant regulatory element sequences contained in their
promoters (60).

It is well established that iron progressively accumulates in

the brain with age, as well as in those brain areas affected by
neurodegenerative diseases, and is considered to be a major
contributor to OS (7,61). Transcranial sonography has detected
increased iron and decreased neuromelanin levels at the sub-
stantia nigra, even before the clinical manifestation of PD (62).

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Similarly, analysis of AD brains indicates iron accumulation
within specific brain regions displaying selective vulnerability
to neurodegeneration, such as the hippocampus and cerebral
cortex (63,64), in particular in association with neurofibrillary
tangles and Alzheimer’s Ab-containing senile plaques, both
considered central pathological hallmarks of AD.

These observations have formed the basis for the implementation

of iron-complexing molecules that can cross the blood-brain
barrier and possess neuroprotective/neurorestorative activities
as a new therapeutic approach in neurologic disorders. Exam-
ples include the novel nontoxic lipophilic, brain-permeable
multifunctional iron chelators HLA20 and M30, in which the
N-propargylamine neuroprotective moiety of the antiparkinso-
nian drug rasagiline was incorporated into the skeleton of the
prototype iron chelator 8-hydroxyquinoline derivative VK28
(Varinel, West Chester, PA) [for review see Youdim and Buccafusco
(65)]. Recent lines of research reported that several metal-binding
natural antioxidants, including polyphenols of wine (e.g., resver-
atrol, myricetin, quercetin, kaemferol), curcumin, (1)-catechin,
(2)-epicatechin, nordihydroguaiaretic acid, and rosmarinic acid
inhibit formation of nascent Ab and a-synuclein fibrils, elongation
of the fibrils, and destabilization of the formed assemblies (66,67),
suggesting a promising therapeutic approach of naturally occur-
ring polyphenols for the treatment of neurodegenerative diseases.

In light of the multietiological character of neurodegenerative

disease pathology, novel pharmacological approaches suggest
the use of antioxidant metal-chelating molecules possessing 2 or
more active neuroprotective moieties that simultaneously ma-
nipulate multiple desired targets. A wealth of new data suggests
that green tea catechins may well fulfill the requirements for a
putative neuroprotective drug displaying diverse pharmacolog-
ical activities. Originally viewed as simple radical scavengers,
green tea catechin polyphenols are considered at present to be
compounds that invoke a spectrum of cellular mechanisms of
action related to their neuroprotection/neurorescue activities.
These mechanisms may include activation of signaling pathways
(e.g., PKC, MAPK, AKT); promotion of neurite outgrowth;
antioxidant action (direct radical scavenging and induction of
endogenous defenses such as SOD, catalase, and phase II de-
toxifying enzymes); antiapoptotic action (induction/reduction of
survival/death genes, respectively); bioenergetic action (mito-
chondrial stabilization); increase of synaptic DA (by promoting

DAT internalization and inhibition of COMT activity); prefer-
ential processing of APP by a-secretase to engender the
nonamyloidogenic sAPPa; reduction of Ab and a-synuclein
generation/fibrillization and plaque burden (a direct action on
formation of nascent or destabilization of assembled fibrils); and
reduction of membrane-associated APP hippocampal levels,
presumably via the iron-chelating effect on APP mRNA trans-
lation. Thus, EGCG may influence Ab levels, either via trans-
lational inhibition of APP or by stimulation of sAPPa secretion.
It cannot be ruled out that some of the biological effects de-
scribed above may share a common signaling pathway. For exam-
ple, activation of the PKC signaling pathway by EGCG (26,30)
might be responsible for the acute decrease in Bad protein (32)
as well as regulation of DA transporters (48) and elevation of
sAPPa secretion (28). A proposed schematic model for the neuro-
protective/neurorestorative effect by EGCG is illustrated in Fig. 1.

Collectively, the accumulated data support and extend the

emerging view that green tea catechins are multimodal-acting,
brain-permeable natural iron chelators-antioxidants endowed with
polypharmacological activities and acting at multiple brain targets
to prevent or delay neuronal death in the degenerating brain. The
intervention with these compounds is assumed to have a profound
impact on neuron preservation and disease progression. The
presently described neurorescue/neurorestorative action of EGCG
may suggest a potential disease-modifying effect for this polyphenol.

Other articles in this supplement include references (68–77).

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FIGURE 1

Proposed schematic model for

EGCG neuroprotective/neurorescue action.
For explanation see text. Abbreviations: Ab,
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