NBR 391

NEUROSCIENCE AND
BIOBEHAVIORAL
REVIEWS

PERGAMON Neuroscience and Biobehavioral Reviews 23 (1999) 1079–1086

www.elsevier.com/locate/neubiorev

Final common pathways in neurodegenerative diseases: regulatory role of

the glutathione cycle
G.F. Weber*
Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Room SM 718, Boston, MA 02115, USA
Received 18 February 1999; received in revised form 12 July 1999; accepted 19 July 1999

Abstract
Attempts to unify diverse mechanisms of neurotoxicity have led to the concept of final common pathways which characterize frequently
occurring cellular responses to disruption of homeostasis. The clinical presentation and common patho-biochemistry of reactive oxygen
intermediates of Guam’s disease have suggested that such pathways may be operative in three major neurodegenerative disorders: Alzhei-
mer’s dementia, amyotrophic lateral sclerosis and Parkinson’s disease. A candidate-signaling pathway in this regard is characterized by the
cascade arachidonic acid/HPETE/ ·OH/cGMP followed by activation of cGMP-dependent kinase and phosphorylation of NF-kB proteins and
possibly CREB. This sequence may lead to apoptosis as well as long-term potentiation and memory and constitutes a biochemical correlate to
excitotoxicity. The predominant control of ·OH release from HPETE, a checkpoint in this pathway, is exerted by the glutathione cycle, a
central biochemical process that is also intimately associated with the synthesis of the neurotransmitters glutamate and GABA and is
connected to energy metabolism. Modifications in the activity of the glutathione cycle may provide treatment options. q 1999 Elsevier
Science Ltd. All rights reserved.
Keywords: Neurodegenerative diseases; Homeostasis; Glutathione cycle

1. Introduction 2. Biochemical basis

Although it is known that multiple causes may lead to the
three major neurodegenerative diseases: Alzheimer demen-
tia, amyotrophic lateral sclerosis and Parkinson’s disease,
their patho-physiology appears to be linked as evidenced by
the occurrence of symptoms from all three disorders in
Guam’s disease. Furthermore, recent indications attribute
the cell loss in these diseases to apoptosis, a process that
has been intimately associated with signaling involving
reactive oxygen intermediates and is consistent with asso-
ciation of all three syndromes with an imbalance in redox
regulation in the central nervous system. Thus, the involve-
ment of reactive oxygen intermediates in signaling leading
to cell death may constitute a convergence in disease
mechanisms. Such final common pathways characterize
frequently occurring cellular responses to various modes
of disruption of homeostasis for which this study outlines
a candidate biochemical pathway.
* Tel.: 1 1-617-632-4629.
E-mail address: georg_weber@dfci.harvard.edu (G.F. Weber)
0149-7634/99/$ - see front matter q 1999 Elsevier Science Ltd. All rights reserved.
PII: S0149-763 4(99)00041-X
2.1. Pathways to memory
Ligation of the NMDA receptor by glutamate mediates
signals leading to long-term potentiation. The biochemical
steps involved in this signal transduction cascade include
phospholipase A, reactive oxygen intermediates, and cyclic
guanosine monophosphate (cGMP) [1] and are consistent
with a pathway in which arachidonate is released, converted
to hydroperoxyeicosatetraenoate (HPETE) which releases
hydroxyl radicals that activate guanylate cyclase, the
production of cGMP activates cGMP-dependent kinase,
which phosphorylates and activates transcription factors
(Fig. 1a). In addition, a cascade of calcium/calmodulin-
dependent activation of nitric oxide synthetase and nitric
oxide production is mediated through the NMDA receptor
[2]. cGMP-dependent kinase activity that can also be
induced by nitric oxide has been demonstrated in the hippo-
campus and modifiers of this enzyme can modulate induc-
tion of long-term potentiation [3]. The transcription factor
CREB is a likely substrate for cGMP-dependent kinase that
has been shown to enhance memory [4]. It may be important
to note that arachidonate, nitric oxide and carbon monoxide,
1080 G.F. Weber / Neuroscience and Biobehavioral Reviews 23 (1999) 1079–1086
 G.F. Weber / Neuroscience and Biobehavioral Reviews 23 (1999) 1079–1086 1081

Table 1
Pathobiochemistry of Alzheimer’s disease. Known genetic risk factors commonly elevate amyloid formation and induce oxidative stress that may lead to
programmed cell death. Since amyloid itself can transduce apoptotic signals in neurons, two modes of induction of cell death may synergize. APP: amyloid
precursor protein, Ab: amyloid b, PS: presenilin, ApoE: apolipoprotein E, RAGE: receptor for advanced glycation end products

Risk Defect Contribution to amyloid Oxidative stress/apoptosis

factors formation

APP Point mutations, loss Precursor of amyloid Potential generator of reactive oxygen species,
of bases in mRNA apoptosis through binding of Ab to RAGE
PS1, PS2 Missense, in frame Increased levels of Ab 42/43 Defect of anti-apoptotic gene product
deletion
ApoE Allelic variation Lack of Ab binding activity Lack of anti-oxidant

all inducers of guanylate cyclase, are also candidate retro-
grade messengers in long-term potentiation implying the
possibility that identical pathways are operative presynapti-
cally and postsynaptically. This pathway is relevant for
induction of long-term potentiation, while protein kinase
C (PKC) causes maintenance of long-term potentiation,
and protein kinase C can be induced by calcium, arachido-
nate, and reactive oxygen species (Fig. 1b).
The intracellular signaling cascade mediating long-term
potentiation is negatively regulated by glutathione peroxi-
dase, which can prevent the release of hydroxyl radical from
HPETE by enzymatic conversion to hydroxyeicosatetraeno-
ate (HETE). In functional synergism, 12-lipoxygenase is
directly inhibited by reduced glutathione [5]. Therefore,
the release of hydroxyl radical can be considered to be a
checkpoint that is controlled by the glutathione cycle. Short-
term memory capacity may be a readout for long-term
potentiation and has been associated with intelligence [6].
The link between the long-term potentiation and memory
[3] suggests that glutathione may contribute to intellectual
performance by limiting the glutamate-dependent signal
transduction to sub-excitotoxic levels (see later). This
may, in part, explain the observed correlation between
glutathione peroxidase levels and intelligence [6].
2.2. Pathways to apoptosis
The concept of excitotoxicity is based on the hypothesis
that common receptors mediate both excitation and toxicity
in neurons. Interestingly, a pathway similar to the one asso-
ciated with induction of long-term potentiation has been
attributed to programmed cell death in T-lymphocytes
[7,8] and has been inferred from studies of TNF-receptor-
dependent signaling [9–11] and engagement of the Fas anti-
gen [12]. Two markers of oxidative stress in the central
nervous system, expression of heme oxygenase-1 and
nuclear localization of NF-kB p50 [13], are intimately asso-
ciated with the outlined pathway because heme oxygenase-1
may activate cGMP kinase [7] while the NF-kB proteins p50
and p49 are substrates for this enzyme (Weber, unpublished
results). Cyclic GMP-dependent kinase also induces expres-
sion of c-Fos, possibly via activation of SRE, CREB or FAP
[14]. Glutathione has been shown to prevent various forms
of programmed cell death, which are associated with
increased levels of reactive oxygen species in signaling
[15]. This is accomplished by the redox cycle catalyzed
by glutathione peroxidase and glutathione reductase,
which can scavenge reactive oxygen intermediates, includ-
ing HPETE, during glutathione oxidation. In conjunction
with direct inhibition of 12-lipoxygenase by glutathione
[5] this mechanism may account for protection from
excitotoxicity.
3. Neurodegenerative diseases linked by pathology of
reactive oxygen species
3.1. Alzheimer’s disease
Known genetic risk factors for familial Alzheimer’s
disease have been localized to the amyloid precursor
protein, apolipoprotein E, presenilin 1 and presenilin 2
genes. Common mechanisms of action of these diverse
molecules include regulation of amyloid production and of
the metabolism of reactive oxygen intermediates so that
malfunctioning of these gene products causes elevated
generation of amyloid b protein and of reactive oxygen
species (Table 1). The increased oxidative stress may sensi-
tize neurons to the apoptotic signals induced by amyloid
(see later), creating a double burden.
Presenilins (PS1 and PS2) contribute to the regulation of
apoptosis, with the wild-type of Alzheimer’s gene STM2

Fig. 1. A biochemical pathway describing redox regulation of signal transduction may be engaged after ligation of various receptors in cells of diverse
specification. This signaling cascade may mediate transient activation followed by programmed cell death. PLA2: phopholipase A2, PLC: phospholipase C,
DAG: diacyl glycerol, AA: arachidonic acid, PKC: protein kinase C, GPX: glutathione peroxidase, NOS: NO synthetase, LTP: long-term potentiation. (a)
General outline of a pathway that is widely used and may lead to apoptosis or—in the central nervous system—to long-term potentiation. (b) Memory in the
central nervous system may depend on the pathway outlined in (a) insofar as induction (solid arrows) of long-term potentiation is concerned. Maintenance
(dashed arrows) of long-term potentiation is mediated by protein kinase C which can be activated by calcium, arachidonate, or hydroxyl radical from the
pathway to induction.
1082 G.F. Weber / Neuroscience and Biobehavioral Reviews 23 (1999) 1079–1086

Fig. 2. Regulatory pathways affected in Alzheimer’s disease share two common mechanisms, control of amyloid b secretion and of oxidative stress leading to
apoptosis. The mechanism of apoptosis induction by amyloid b converges with the signal transduction cascade that mediates long-term potentiation and may
result in excitotoxicity which would account for the loss of memory.

(PS2) exerting anti-apoptotic effects [16]. Presenilins
undergo regulated endoproteolytic processing. During
apoptosis, they may be cleaved distal to their normal cleav-
age sites and a mutation in presenilin 2 that is related to
familial Alzheimer’s disease favors this alternative cleavage
which may either directly enhance apoptosis or diminish the
apoptosis regulating function of the wild-type fragments
[17]. Furthermore, a complex of presenilin and b- or d-
catenin can activate g-secretase, the enzyme that releases
the amyloid fragment Ab(1-42), with a consequent increase
in the excreted amyloid b. Apolipoprotein E (ApoE)
protects neurons from hydrogen peroxide toxicity and
binds specific metal ions, including iron, which could other-
wise catalyze the generation of hydroxyl radicals. The gene
product of apolipoprotein E allele epsilon 4 has decreased
anti-oxidant activity compared to alleles epsilon 2 and 3
[18]. Apolipoprotein E may also protect from b-amyloid
peptide toxicity by binding to amyloid b and, under certain
circumstances, acting as kinetic inhibitor of amyloid forma-
tion [18].
The major proteinaceous component of plaques is b-
amyloid, the abnormal cleavage product of the amyloid
precursor protein (APP). Various metals can bind to
amyloid precursor protein and influence its conformation,
stability, and homophilic interactions. APP may bind copper
and catalyze a redox reaction that reduces Cu(II) to Cu(I)
and gives rise to cystine formation in the amyloid precursor
protein. Once Cu(I) is formed, it may, in the presence of
peroxides, produce activated oxygen species including
superoxide and hydroxyl radical [19]. It is currently
unknown whether the binding of zinc, which can lead to
precipitation of amyloid protein [20], may also be asso-
ciated with changes in the homeostasis of reactive oxygen
species. While the function of amyloid precursor protein as
a free radical generator may contribute to affecting neuron
viability, the concentrations of amyloid b required to gener-
ate free radicals are, in general, moderately high [21] imply-
ing that the importance of this mechanism in vivo may have
been overestimated. Furthermore, the accumulation of inter-
cellular masses of amyloid, in contrast to the soluble mole-
cules, is not suitable to induce signals in neurons. An
alternative mechanism by which amyloid b may cause
oxidative stress in neurons as well as activation of microglia
cells is via binding to a cell surface receptor for advanced
glycation end products (RAGE) [13]. This receptor can also
be engaged by amphoterin and is physiologically involved
in neurite outgrowth. Signal transduction through RAGE
may increase lipid peroxidation as well as activation of
 G.F. Weber / Neuroscience and Biobehavioral Reviews 23 (1999) 1079–1086
Fig. 3. The glutathione cycle. The turnover of glutathione involves the
intracellular synthesis from glutamate, cysteine and glycine. Glutathione is
then transported and converted by membrane-bound g-glutamyl transpep-
tidase followed by cleavage by membrane-bound dipeptidase. g-Glutamyl
amino acids are transported into the cell and converted to glutamate via
oxoproline. Glutathione is synthesized from glutamate by addition of
cysteinyl- and glycyl-residues [49].
NF-kB p50 [22]. It can be suppressed by N-acetylcysteine
[23] and inhibition of lipoxygenase protects hippocampal
neurons from amyloid b toxicity [24]. These data imply a
pathway outlined in Fig. 1 to be associated with RAGE. The
oxidative stress generated via production of free radicals by
amyloid or via amyloid-dependent signaling can be
increased by the common risk factors through elevated
release of Ab and through directly inflicted oxidative stress
and apoptosis (Fig. 2).
3.2. Amyotrophic lateral sclerosis
Glutamate signaling through the NMDA receptor
involves the generation of hydroxyl radical, excess of
which may be excitotoxic. Like the NMDA receptor, liga-
tion of the kainate receptor by glutamate may induce the
generation of reactive oxygen species, nitric oxide and
cyclic GMP [25,26] even though the two signal transduction
pathways differ proximally. Selective neuron degeneration
in amyotrophic lateral sclerosis may be caused by gluta-
mate-mediated excitotoxicity [27] with ligation of kainate
receptors as contributing mechanism. One possible cause is
an altered presynaptic process due to reduced glutamate
dehydrogenase that would lead to elevated levels of gluta-
mate in the synaptic cleft [28]. This could give rise to
mutual enhancement of glutamate toxicity and oxidative
stress by two mechanisms. Firstly, reactive oxygen species
may inhibit high affinity glutamate uptake thus increasing
the synaptic glutamate concentration [26]. Secondly, contin-
uous exposure of cells to glutamate inhibits cystine uptake
via the glutamate/cystine anti-porter and thus reduces cellu-
lar glutathione resynthesis [29,30], which predisposes to
1083
oxidative damage. Motor neurons may be the selected target
because of their direct glycinergic innervation since glycine
prevents desensitization of the NMDA receptor to this
ligand thus abnormally enhancing glutamatergic transmis-
sion [31].
Some cases of familial amyotrophic lateral sclerosis are
characterized by mutations of copper–zinc superoxide
dismutase. It may not be immediately obvious why muta-
tions of an enzyme that serves protective functions through-
out the organism would selectively lead to amyotrophic
lateral sclerosis as opposed to a broader range of disease
phenotypes. This question arises particularly in view of
the observation that superoxide dismutase activities in
erythrocytes from patients may be reduced by 50%
compared with healthy controls [27]. The relevant muta-
tions appear to be pathogenic due to a gain in adverse
function rather than a loss of superoxide dismutating
activity and are independent of the activity of the
wild-type enzyme [32]. Superoxide dismutase may act
as a peroxidase [33,34] with mutated superoxide dismutase
catalyzing substrate oxidation by hydrogen peroxide at a
higher rate than wild-type enzyme [35]. This hydrogen
peroxide-dependent substrate oxidation leads to signals
that mediate the release of arachidonate [36] which, in addi-
tion to its contribution to apoptotic signaling, may inhibit
the uptake of glutamate from the synaptic cleft [26,37,38].
This predominantly affects motor neurons because their
direct glycinergic innervation prevents desensitization of
the NMDA receptor (see earlier).
3.3. Parkinson’s disease
Increased turnover of dopamine in catecholaminergic
neurons may lead to the generation of hydrogen peroxide
during dopamine desamination and its consecutive reduc-
tion to hydroxyl radical catalyzed by melanin chelated iron
[39,40]. Excess hydroxyl radical can mediate signals lead-
ing to programmed cell death and the resulting loss of
neurons may induce a vicious circle by compensatory upre-
gulation of dopamine turnover in the surviving neurons.
Signal transduction through dopamine D2 receptors also
activates phospholipase A2 with consecutive release of
arachidonate [41] and the biochemical consequences
described in Fig. 1a. The highest brain peroxidase activity
in healthy individuals is localized in the substantia nigra and
particulate glutathione peroxidase activity is highest in the
basal nucleus and amygdala [42]. Peroxidase and catalase
activities are reduced in the substantia nigra, caudate, and
putamen in Parkinson’s disease [43]. A marked reduction in
glutathione has been observed [44–46] and Riederer et al.
[47] reported significantly lower glutathione content in the
basal ganglia. This is consistent with experimental results
where depletion of glutathione increased dopamine toxicity
[48] demonstrating the protective role of glutathione
(Fig. 4).
1084 G.F. Weber / Neuroscience and Biobehavioral Reviews 23 (1999) 1079–1086

Fig. 4. Central role of the glutathione cycle in the regulation of signal transduction for long-term potentiation or apoptosis. The glutathione cycle is also
associated with energy metabolism and with the synthesis of neurotransmitters. The biochemical reactions associated with dopamine metabolism are shaded
dark, the glutathione cycle has an intermediate shade, and the signal transduction pathway associated with the NMDA receptor is shown in light gray shade.
Furthermore, the involvement of glutathione in the hexose monophosphate shunt (HMS) is pointed out and the relationships of glutamate with the g-amino
butyrate (GABA) shunt and the tricarboxylic acid cycle are depicted.

4. Regulating function of the glutathione cycle
The engagement of identical biochemical pathways for
cellular activation and for programmed cell death poses the
unique hazard of excitotoxicity. The release of hydroxyl
radical in the signaling cascade may serve as a checkpoint
in this context. A central regulatory role in the scheme of
redox regulation is played by glutathione peroxidase, the
enzyme that may convert HPETE to HETE. Glutathione
peroxidase is part of the glutathione cycle (Fig. 3), a ubiqui-
tous metabolic pathway that includes intracellular synthesis
of glutathione, transport, extracellular reactions, and re-
uptake of g-glutamyl-amino acids and cysteine. The
glutathione cycle [49] is an important biochemical process
that contributes critically to homeostasis of the intermediary
metabolism of reactive oxygen species through reduction of
disulfide linkages of proteins in many cell types. Further-
more, around 10% of cellular glutathione peroxidase are
mitochondrial and there prevent oxidative damage by
hydrogen peroxide. It is also linked to the mitochondrial
respiratory chain through its close relation to the tricar-
boxylic acid cycle that supplies succinate for this process.
In addition, it regulates energy metabolism by its associa-
tion with the hexose monophosphate shunt. The glutathione
cycle may serve regulatory functions in intra- and intercel-
lular signaling in the central nervous system where it is
linked to uptake and metabolism of glutamate and to the
synthesis of g-aminobutyrate (Fig. 4).
The regulatory role of the glutathione cycle is particularly
important in the central nervous system because deficiency
of enzymes associated with it (glutathione synthetase, g-
glutamyl synthetase, or g-glutamyl transpeptidase) leads
 G.F. Weber / Neuroscience and Biobehavioral Reviews 23 (1999) 1079–1086
to defective brain function [49,50] in addition to acidosis
and a tendency to hemolysis. Glutamate is part of the g-
amino butyrate-shunt, which synthesizes the cerebellar inhi-
bitory transmitter g-aminobutyrate. Reduced activities in
glutamate decarboxylase and g-amino butyrate in senile
dementia and Huntington chorea might be caused, in part,
by reduced concentrations of the substrate glutamate due to
affection of the glutathione cycle. The pathways outlined in
this study are also consistent with alternative causative
agents for neurodegenerative diseases. These include occu-
pational exposure for Alzheimer’s disease for which pathol-
ogies related to reactive oxygen species have been
described. The deleterious effect of manganese on the
basal ganglia has been postulated to be by way of catalysis
of dopamine oxidation with consecutive oxidative stress. 1-
Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) may
cause Parkinson’s disease through free radical reactions
and mice deficient in phospholipase A2 are resistant to its
neurotoxicity. The possibility of nutritional uptake of a
neurotoxin as underlying cause for Guam’s disease has
been proposed and would be in keeping with the above
model.
Different symptoms after disruption of redox homeostasis
in the neurodegenerative diseases discussed here may be
due to various levels of activity in individual parts of the
outlined pathways in different brain regions, such as long-
term potentiation in the hypothalamus and dopamine synth-
esis in basal ganglia. Iron-catalyzed generation of reactive
oxygen intermediates is likely to play a more significant role
in Parkinson’s disease than in other neurodegenerative
disorders since the concentration of iron is particularly
high in the basal ganglia. Conversely, apoptosis through
redox mechanisms that activate cGMP-dependent kinase
affect predominantly the hypothalamus where this pathway
is physiologically engaged at low levels, while the glyciner-
gic innervation of motor neurons makes them particularly
susceptible to excess of synaptic glutamate. Hence, the main
anatomical locus of action by a noxious influence depends
on its biochemical targets and determines the disease symp-
toms. Various clinical pictures in response to one neuro-
toxin might also be dose-dependent or caused by changing
susceptibility of different brain areas during development
and aging. The common regulatory role of the glutathione
cycle may provide a potential therapeutic target.
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