Seiler Ammonia and Alzheimer's Disease

Neurochemistry International 41 (2002) 189207
Review
Ammonia and Alzheimers disease

Nikolaus Seiler
Laboratory of Nutritional Oncology, Institut de Recherche Contre les Cancers de lAppareil Digestif (IRCAD), Strasbourg, France
Abstract
Alzheimers disease (AD) is the most common age-related neurodegenerative disorder. Behavioural, cognitive and memory dysfunctions
are characteristic symptoms of AD. The formation of amyloid plaques is currently considered as the key event of AD. Other histological
hallmarks of the disease are the formation of fibrillary tangles, astrocytosis, and loss of certain neuronal systems in cortical areas of the
brain. A great number of possible aetiologic and pathogenetic factors of AD have been published in the course of the last two decades.
Among the toxic factors, which have been considered to contribute to the symptoms and progression of AD, ammonia deserves special
interest for the following reasons: (a) Ammonia is formed in nearly all tissues and organs of the vertebrate organism; it is the most common
endogenous neurotoxic compounds. Its effects on glutamatergic and GABAergic neuronal systems, the two prevailing neuronal systems
of the cortical structures, are known for many years. (b) The impairment of ammonia detoxification invariably leads to severe pathology.
Several symptoms and histologic aberrations of hepatic encephalopathy (HE), of which ammonia has been recognised as a pathogenetic
factor, resemble those of AD. (c) The excessive formation of ammonia in the brains of AD patients has been demonstrated, and it has
been shown that some AD patients exhibit elevated blood ammonia concentrations. (d) There is evidence for the involvement of aberrant
lysosomal processing of -amyloid precursor protein (-APP) in the formation of amyloid deposits. Ammonia is the most important natural
modulator of lysosomal protein processing. (e) Inflammatory processes and activation of microglia are widely believed to be implicated
in the pathology of AD. Ammonia is able to affect the characteristic functions of microglia, such as endocytosis, and cytokine production.
Based on these facts, an ammonia hypothesis of AD has first been suggested in 1993. In the present review old and new observations are
discussed, which are in support of the notion that ammonia is a factor able to produce symptoms of AD and to affect the progression of
the disease. 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Alzheimers disease; Bloodbrain barrier; Hepatic encephalopathy; Cerebrospinal fluid
1. Alzheimers disease is a multifactorial disease

with a complex aetiology
Alzheimers disease (AD) (senile dementia of the
Alzheimer type) is the most common neurodegenerative
disorder, accounting for about 70% of all cases of senile
dementia. Fiveten percent of people over the age of 60,
and 2040% of people over the age of 80 are victims of
late onset AD. Owing to the increasing life-expectance
of the population, AD belongs among the most pressing
socio-medical problems of our day.
Abbreviations: -APP, -amyloid precursor protein; ATP, adenosine triphosphate; CSF, cerebrospinal fluid; GABA, 4-aminobutyric acid;
GS, glutamine synthetase; cGMP, cyclic guanosine monophsophate; GTP,
guanosine triphosphate; HE, hepatic encephalopathy; MAO, monoamine
oxidase; NMDA, N-methyl-d-aspartate; NO, nitric oxide; PET, positron
emission tomography
Present address: INSERM U392. IRCAD, 1, place de lH
opital, 67091
Strasbourg Cedex, France. Tel.: +33-3-88-119030; fax: +33-3-88-119097.
E-mail address: nikolaus.seiler@ircad.u-strasbg.fr (N. Seiler).
Both, dominantly inherited familial (early onset), and late

onset AD are clinically characterised by the gradual impairment of behavioural and cognitive functions, and memory
loss. The diagnosis of AD is preceded by a long preclinical
phase in which deficits in memory performance are most
common (Small et al., 2000). Neuropathologically, AD is
characterised by the loss of various neuronal populations
(Davies and Maloney, 1976; McGeer et al., 1984; Palmer and
DeKosky, 1993), the presence of neurofibrillary tangles and
amyloid plaques in hippocampus and cortical areas (Selkoe,
1991; Crowther, 1993; Yankner, 1996; Haass, 1998), associated with reactive or fibrous astrocytes (Frederickson,
1992). Activation of microglia is a result of brain inflammatory processes (McGeer and McGeer, 1998; Popovic et al.,
1998; Gahtan and Overmier, 1999). Other histopathological aberrations include reduction in the density of neuronal
insulin receptors (Hoyer et al., 1996; Frlich et al., 1999),
and of neurotransmitter receptors of various types: muscarinic and nicotinic acetylcholine receptors (Ogawa et al.,
1993; Pavia et al., 1996; Giacobini, 1991), and receptors of
0197-0186/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved.
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N. Seiler / Neurochemistry International 41 (2002) 189207
serotonin, dopamine, 4-aminobutyric acid (GABA), and glutamate (DeKeyser, 1992; Greenamyre and Maragos, 1993;
Blin et al., 1993; Joyce et al., 1993; Soricelli et al., 1996;
Mizukami et al., 1998; Carlson et al., 1993; Palmer and
DeKosky, 1993).
Although amyloid plaques and neurofibrillary tangles are
neuropathological hallmarks of AD, a poor correlation between the degree of dementia and the severity of these pathological lesions was found. It appears that losses of synapses
due to neuronal losses (presumably by apoptotic cell death
(Stadelmann et al., 1999; Yuan and Yankner, 2000) are better structural correlates of dementia than other brain lesions
(Lassmann, 1996).
The aetiology of AD is complex and multifactorial. The
influence of genetic factors on the pathogenesis of the disease has been shown by family and twin studies (Jarvik
et al., 1980; Heston, 1989; Farrer et al., 1989; Hocking and
Breitner, 1995). Genetic factors influence both age at onset
and age at death (Lippa et al., 2000; Tandon et al., 2000). The
discovery that 4 allele of lipoprotein E is a normal polymorphism (Strittmatter and Roses, 1995), and the discovery of
the polymorphism in the gene encoding 2-macroglobulin,
a large multifunctional protein that can act as protease inhibitor, led to the suggestion that these genetic changes
represent increased risks of late onset AD (Blacker et al.,
1998; Korovaitseva et al., 1999). Up to now four genes have
been identified in dominantly inherited familial AD, with
mutations of -amyloid precursor protein (-APP), and of
presenilin-1, and presenilin-2 genes (Blacker and Tanzi,
1998). These genes cause the elevation of brain levels of
the self-aggregating amyloid- protein, and appear to cause
neuronal and glial alterations, synaptic loss, and dementia by
a sequence of steps, as reviewed by Selkoe (1999) (Fig. 1).
Risk factors of AD increase with age. Therefore, general age-related changes in organ function and metabolism
have to be taken into consideration as contributing factors. For example brain vulnerability to -APP increases
with age (Geula et al., 1998). The age-related impairment
of bloodbrain barrier function is of special importance,
even though it has been shown that it is equally impaired in AD and non-demented elderly (Alafuzoff et al.,
1987; Harik and Kalaria, 1991). In patients with AD
combined with multi-infarct dementia bloodbrain barrier
damage is more accentuated than in age-matched controls
Fig. 1. A hypothetical sequence of pathogenetic steps of familial forms of Alzheimers disease (according to Selkoe, 1999, modified).
(Leonardi et al., 1985). Following a dysfunction of the

bloodbrain barrier, the exposure of the brain to exogenous neurotoxins increases. Aluminium (Markesbery et al.,
1981; Thompson et al., 1988; Deloncle and Guillard,
1990; Good and Perl, 1993), and infections by spirochetes
(Miklossy et al., 1994), prions and viral agents (Prusiner,
1984; Roberts et al., 1986; Price et al., 1993), have been implicated. In addition, endogenous neurotoxins and metabolites including cytokines (Vandenbeele and Fiers, 1991;
Berkenbosch et al., 1992), radicals (Jeandel et al., 1989;
Volicer and Crino, 1990; Smith et al., 1991; Richardson,
1993; Friedlich and Butcher, 1994, Markesbery, 1999),
glutamate (Maragos et al., 1987; Greenamyre et al., 1988;
Cowburn et al., 1990; Advokat and Pellegrin, 1992), a
colchicin-like factor (Gorenstein, 1987), proteoglycans
(Celesia, 1991), and ammonia (Seiler, 1993), have been
discussed as potential pathogenetic factors of AD. The lack
of trophic factors and hormones, e.g. nerve growth factor
(Hefti and Schneider, 1991; Olson, 1993), and somatostatin
(Bissette and Myers, 1992; Gabriel et al., 1993) was also
considered. Finally, a cobalaminergic hypothesis of AD was
published (McCaddon and Kelly, 1992).
A number of metabolic and functional deficits in
Alzheimer brains have been identified, among which the
impairment of glucose and energy metabolism appears most
important (Heiss et al., 1991; Mielke et al., 1992; Meneilly
and Hill, 1993; Hoyer, 1993; Swerdlow et al., 1994;
Simpson et al., 1994; Meier-Ruge et al., 1994; Bottomley
et al., 1992; Simonian and Hyman, 1993; Chandrasekaran
et al., 1994). But aberrant G-protein mediated signal transduction (Fowler et al., 1992; Joseph et al., 1993; Saitoh
et al., 1993), aberrant phosphoinositide and ganglioside
metabolism, (Shimohama et al., 1993; Svennerholm, 1994)
and membrane dysfunctions (Nitsch et al., 1992; McClure
et al., 1994; Cowburn et al., 1995) have also been discussed. Alterations in brain monoamine oxidase (MAO;
E.C.1.4.3.4) activity (Sparks et al., 1991; Jossan et al.,
1991), and changes in neurotransmitters and second messengers (Francis et al., 1993; Nordberg, 1993) may also
contribute to the symptomatology and progression of AD.
The earlier quoted papers represent only a small fraction
of the literature on AD. They give an idea of the multitude of
attempts that have been made in the past to elucidate aetiology and pathogenesis of AD, and indicate a rather complex
multifactorial disease. It is not intended to evaluate the relative merits of the divergent observations and ideas that have
been published in the course of the years concerning potential pathogenetic factors of AD. In fact, much of the work
has been widely ignored by the scientific community, or remained at a preliminary stage. The breath-taking progress in
the elucidation of the molecular biology of amyloid plaque
formation, and of functions of the presenilins in the highly
complex Notch pathway (Haass, 1998; Selkoe, 2000a,b), has
left little support for alternative approaches to AD.
Among the neurotoxic agents, which have been discussed
in connection with AD pathology, ammonia is unique. It is
191
nearly ubiquitous in nature, and is the product of several reactions, which are active in most cells and organs. Sophisticated elimination and detoxification mechanisms have been
developed during evolution by most organisms in order to
prevent the excessive accumulation of ammonia, indicating
its dangerous qualities, but at the same time its universal importance. It is for this reason that ammonia deserves special
attention in pathologic conditions.
2. Ammonia is elevated in blood and brain of

patients with Alzheimers disease
The precise determination of free ammonia in tissues
and body fluids is difficult, in part because of the danger
that bound ammonia is liberated. Therefore, reported values
show considerable variations. For arterial blood plasma of
healthy volunteers 70113 nmol/ml concentrations of ammonia have generally been reported. Cerebrospinal fluid
(CSF) and venous blood ammonia concentrations are within
the same range (20100 nmol/ml) (Cooper and Plum, 1987).
Excessive ammonia is usually rapidly taken up from the
blood by most organs, including the brain, and removed by
formation of glutamine. In liver glutamine is hydrolysed and
ammonia is transformed into urea and eliminated via the
kidneys.
Fisman et al. (1985, 1989) reported that post-prandial
blood ammonia levels in 22 patients with AD were significantly higher than in 37 age-matched control subjects. Within the AD group, fasting blood ammonia levels
were significantly higher in patients whose EEG showed
tri-phasic waves, as compared with patients that did not
exhibit this wave form. Tri-phasic waves are suggestive of
hepatic encephalopathy (HE).
Branconnier et al. (1986) found 122 80 nmol ammonia/ml plasma in subjects with AD. The normal range in this
study was 1255 nmol/ml. Eighty-three percent of the AD
patients had blood ammonia levels above the normal range.
All participants in these studies were free of liver diseases,
and urinary tract infections, i.e. exogenous ammonia sources
were not responsible for the elevated blood concentrations.
Owing to rapid post-mortem formation of ammonia, no
data on brain ammonia of AD patients exist. However, determinations of arteriovenous differences (Hoyer et al., 1990)
in patients with advanced AD demonstrated that 27 3 g
ammonia/min kg brain were released into the periphery.
From the brains of patients with clinically diagnosed early
onset dementia (most probably subjects with early onset AD)
256 162 g ammonia/min kg brain were released. In striking contrast, the brains of healthy volunteers retained ammonia from the arterial blood at a rate of 72 7 g/min/kg.
Since ammonia has not attracted much attention as a factor
possibly implicated in the pathology of AD, no new data on
blood ammonia concentrations have been reported since the
first publication of the ammonia hypothesis (Seiler, 1993).
Nevertheless, the earlier quoted observations allow one to
192
conclude that in addition to an age-related impairment of

liver function, i.e. a reduced capacity of the liver to form
urea, there is an AD-related cause of hyperammonemia. The
arteriovenous differences are evidence for pathological ammonia metabolism in the brains of AD patients. Deficient
astrocytic glutamine formation, or enhanced formation of
ammonia, or both, could contribute to the excessive release
of ammonia from AD brains.
3. In Alzheimers disease brain ammonia

metabolism is impaired
Ammonia is a normal metabolite of all tissues. In addition,

it can be taken up from the gastrointestinal tract. Since it is a
highly neurotoxic agent, the removal of excessive amounts of
ammonia from the vertebrate organism is critical. Within the
mammalian tissues and organs ammonium salts (NH4 + ) and
ammonia (NH3 ) are in equilibrium; 98.3% are (at pH 7.4)
present in the protonated form. (ammonia is used in this
text to designate both free and protonated ammonia, keeping
the physiological equilibrium between NH4 + and NH3 in
mind). The non-protonated form passes membrane barriers,
including the bloodbrain barrier, by diffusion; ammonia
accumulation in brain is, therefore, possible in spite of a
barrier function for NH4 + . (For reviews of the physiology
of ammonia see Cooper and Plum (1987), Cooper (1994),
Kvamme (1983)).
In brain, the urea cycle is not functional. The adenosine triphosphate (ATP)-dependent formation of glutamine
by glutamine synthetase (l-glutamate:ammonia ligase
(ADP-forming; E.C.6.3.1.2) (GS) (Fig. 2.) in astrocytes,
and its release into the blood stream is nearly exclusively
responsible for the limitation of brain ammonia concentrations (Cooper and Plum, 1987; Kvamme, 1983). In liver
(and in neurones), glutamine is hydrolysed by glutaminase
(l-glutamine amidohydrolase (phosphate-activated); EC
3.5.1.2) to glutamic acid and ammonia. The latter is transformed in liver into urea, which is excreted, as has been
mentioned.
The increase of brain ammonia concentrations with age
is a general phenomenon, presumably because astroglial GS
activity decreases with age. In the present context it is of
particular importance that patients with AD have significantly lower brain GS activities than age-matched controls
(Smith et al., 1991). Spatially, the decrease of GS activity
correlated with the density of amyloid deposits and senile
plaques in the temporal cortex of AD brains (Le Prince et al.,
1995). Since the loss of GS was elevated in gerbil brains
after ischaemia and reperfusiona situation that causes formation of oxygen radicals (Oliver et al., 1990), and since the
age-related loss of GS synthetase activity (as well as the loss
in temporal and spatial memory) was prevented by chronic
administration of a spin-trapping compound (Carney et al.,
1991), it was suggested that oxidatively-induced structural
alterations of GS are responsible for the enzyme loss Smith
et al., 1992. By using in vitro models it was demonstrated
that the interaction of GS with amyloid- peptide (140)
and amyloid- peptide (2535) resulted in both the oxidative inactivation of GS due to radical formation and an increase of amyloid- peptide neurotoxicity. In hippocampal
cell cultures, the GSamyloid- peptide interaction was accompanied by fibril formation and partial fragmentation of
the peptide (Aksenov et al., 1997). These observations suggest a relationship between amyloid plaque formation and a
compromised ammonia detoxification.
In a recent paper, Robinson (2000) confirmed a decreased
GS activity in astrocytes in the vicinity of senile plaques
of AD inferior temporal cortex. Strikingly, however, GS
was found in a sub-population of pyramidal neurones of
AD brains, but not in brains of age-matched, non-demented
subjects. GS was also detected in the CSF of AD patients
(Gunnersen and Haley, 1992; Tumani et al., 1999). The exact source of the CSF GS is unknown. For obvious reasons
the authors of these papers suggested astrocytic origin. The
observation of Robinson (2000) may, however, hint at neuronal origin. In contrast with GS, the phosphate-activated
glutaminase is unchanged in the brains of AD patients
(Procter et al., 1988). It is well known that the activity
of this enzyme is regulated by ammonia. Interestingly,
glutaminase from brains of young rats is much more sensitive to feed-back regulation by ammonia than the enzyme
from brains of aged animals (Wallace and Dawson, 1992).
From this age-related change in glutaminase properties it
is expected that elevated ammonia concentrations are less
efficient in suppressing intra-neuronal ammonia formation
from glutamine in the aged brain, i.e. ammonia should ac-
Fig. 2. ATP-dependent formation of glutamine, and its hydrolysis to glutamate (astrocyteneuron glutamate trafficking).
cumulate to unusually high concentrations within neurones.

This may trigger the unexpected expression of GS in these
cells, as a compensatory reaction to the toxic stimulus of
elevated ammonia concentrations.
4. Is ammonia formation enhanced in brains of

Alzheimers disease patients?
In vertebrates, ammonia concentrations appear to be
correlated with the functional state of the brain. Reduced
functional activity is associated with reduced ammonia concentrations. Physiological or pathological enhancement of
activity (e.g. electrical stimulation and convulsions) causes
elevated ammonia levels. Hypoxia is also a reason for increased ammonia formation (Kvamme, 1983; Cooper and
Plum, 1987), an aspect, which in view of decreased blood
flow in several cortical areas in AD brains (Ohyama et al.,
1999) should be taken into consideration as a possible
pathological source of ammonia.
The major metabolic sources of ammonia in vertebrates
are summarised in Fig. 3. The brain is in principle not different from other organs with regard to ammonia producing
reactions. Hydrolysis of amido groups of proteins and amino
acids (glutamine, asparagine), deamination of aminopurines,
aminopyrimidines, and of glucosamine-6-phosphate, oxidative deamination of primary amines, and glycine catabolism
via the glycine cleavage system, are well-known endogenous ammonia sources, which contribute to the steady-state
level of brain ammonia (Kvamme, 1983).
193
A considerable amount of ammonia is formed in the gastrointestinal tract (by proteolysis, and by bacteria) from
where it can be taken up into the bloodstream. Deficient hepatic urea formation is a major cause of pathological accumulation of ammonia in brain. Bacterial urinary tract infections
are another cause of hyperammonemic states. Although ammonia and glutamine are excretory products, urea formation
cannot be substituted by excretion or by alternative detoxification mechanisms. Therefore, urea cycle deficits invariably
cause hyperammonemic states with severe pathology.
Up to now only one metabolic source of brain ammonia has been identified, which appears to function at
a pathologically increased rate. Sims et al. (1998) found
that adenosine-3 -monophosphate (AMP) deaminase (EC
3.5.4.6.) activity is 1.62.4-fold greater in the occipital
and temporal cortex and cerebellum of Alzheimer diseased
brains. Elevations of AMP deaminase protein and mRNA
were similar. AMP deaminase is important in the regulation of purine nucleotides. It hydrolyses AMP to inosine
monophosphate and ammonia (Fig. 4). No correlation was
found between the age of control subjects and AMP deaminase activity, i.e. the over-expression of this enzyme appears
to be characteristic of AD.
Although speculative, one further ammonia generating
reaction will be briefly discussed, because of the importance of the enzyme. About 80% of total MAO activity of
the human brain is the MAO B isoform and an age-related
increase of more than 50% has been demonstrated. This increase was even more marked in AD subjects, and has been
related to gliosis (Adolfsson et al., 1980; Nakamura et al.,
Fig. 3. Exogenous and endogenous sources of ammonia in the vertebrate brain.
194
Fig. 4. AMP-deaminase catalysed formation of ammonia.
Fig. 5. Reaction of MAO with a substrate, and radical formation from

hydrogen peroxide.
1990; Jossan et al., 1991). MAO B deaminates oxidatively

numerous primary amines (benzylamine, dopamine, tyramine, tryptamine, -phenylethylamine, etc.). Its products,
aldehyde, ammonia and hydrogen peroxide, are cytotoxic
agents. The latter is also a source of oxygen radicals (Fig. 5).
Due to locally impaired bloodbrain barrier function in AD
patients (Leonardi et al., 1985; Alafuzoff et al., 1987; Harik
and Kalaria, 1991) substrates of MAO B may penetrate into
the brain at an elevated rate, and consequently oxidative
deaminations will increase. Since MAO A activity is also
elevated in the brains of AD patients, though not to the
same degree as MAO B (Sherif et al., 1992), similar considerations are also valid for MAO A and its substrates. One
cannot exclude at present that improvements of cognitive
functions of AD patients during treatment with (R)-deprenyl
(Mangoni et al., 1991) are due to the reduced formation of
the mentioned noxious products of MAO, even though other
explanations are also likely (Boulton, 1999).
5. Manifestations of ammonia toxicity in brain exhibit

analogies to Alzheimers disease pathology
The excessive release of ammonia from brain, the reduced activity of astrocytic GS activity, and the increased
activity of AMP deaminase is direct evidence for an abnormal ammonia metabolism in AD brains. Evidence for a role
of ammonia in the pathology of AD is at present necessarily
indirect. It is suggested by common features of pathologic
manifestations of AD, and diseases with chronically elevated ammonia concentrations. Most of our knowledge of
consequences of chronic hyperammonemia in adult humans
originates from studies of HE, a major neuropsychiatric

complication of acute and chronic liver failure. It is now
accepted that ammonia is a key pathogenetic factor of
HE (Hazell and Butterworth, 1999; Butterworth, 1998a,b,
2000a). However, ammonia may not be the only neurotoxin
of importance in HE. Manganese, e.g. is another candidate
(Hauser et al., 1994), and other factors have been discussed
in the past as well. Typical aberrations common to HE and
AD include the following:
impaired memory and cognitive functions, and behavioural abnormalities (aphasia);
impaired bloodbrain barrier;
astrocytosis;
loss of neuronal systems and receptor abnormalities;
decrease of glucose utilisation;
impaired energy metabolism;
reduced glutamine synthetase activity;
increased extracellular glutamate;
impaired lysosomal processing of proteins.
In HE the source of ammonia is exogenous, and its elevation in brain and other organs is primarily due to the
impairment of liver function. Its distribution in brain is dictated by vascularisation and blood flow. In contrast, in AD
one has to assume localised sources of excessive ammonia
formation in brain. Disregarding these facts, HE and AD
differ also with respect to disease initiation, disease progression and some key histopathologic characteristics, e.g.
amyloid plaques and neurofibrillary tangles are not a characteristic of HE. In view of the common aspects of these
diseases, and the role that is ascribed to ammonia in the aetiology of HE, together with the fact that AD patients have
elevated brain ammonia concentrations, it appears justified
to compare some common features of HE and AD.
6. Ammonia impairs intellectual performance

Cognitive and memory dysfunctions are typical for both
HE and AD. Based on animal experiments it was calculated that a twofive-fold increase of ammonia in brain is
sufficient to compromise the major excitatory (glutamate),
and inhibitory (GABA, glycine) neuronal systems, and to

produce widespread increased neuronal excitability (Raabe,
1987). Bearing this in mind a profound disturbance of brain
functions may not be surprising, especially since it is known
from animal experiments that both hypo-activation and
hyper-activation of glutamatergic neuronal systems causes
impeded cognitive processing (Myhrer, 1998).
Moderate chronic elevation of ammonia concentrations
impairs N-methyl-d-aspartate (NMDA) receptor-dependent
long-term potentiation in the CA1 of hippocampus slices
(Munoz et al., 2000), and compromises active and passive
avoidance behaviour and conditional discrimination learning in rats (Aguilar et al., 2000). The mechanism, which
underlies these learning deficits involves presumably a reduction of nitric oxide (NO)-induced activation of guanyl
cyclase (E.C.4.6.1.3) and glutamate-induced formation of
cyclic guanosine monophsophate (cGMP) (Hermengildo
et al., 1998). In agreement with these findings, neuronal
constitutive NO synthase (1.14.13.39) and protein kinase C
(2.7.1.37) levels were found to be diminished in temporal
regions of AD brains (Gargiulo et al., 2000). Moreover, it
was demonstrated that release of NO into CSF was reduced,
and the decrease in NO formation correlated with the intellectual impairment of AD patients, but not with that of
patients with vascular dementia (Tarkowski et al., 2000).
7. Ammonia and neuronal degeneration

As appears from Fig. 1, the current ideas about the sequellae, which lead to neuronal degeneration in AD brain
are speculative. Inflammatory processes appear to be involved, but the steps which lead from the release of inflammatory proteins and cytokines by astrocytes, microglia and
neurones, as well as the role of the aberrant expression of
NO synthase in perifocal neurones, glial cells (McGeer and
McGeer, 1998; Vandenbeele and Fiers, 1991; Berkenbosch
et al., 1992) and cerebrovascular smooth muscle and endothelial cells (de la Monte et al., 2000) may not be compulsory, although activation of microglia, the macrophages
of the brain, is in the opinion of several investigators an undoubted feature of AD.
A role of ammonia in brain inflammatory processes
has not been suggested. However, ammonia affects major
functional activities (phagocytosis and endocytosis ) of microglia, and astroglioma cell lines; it modifies the release
of cytokines and it increases the activity of lysosomal hydrolases (Atanassov et al., 1994, 1995). These observations
indicate a possible influence of elevated brain ammonia
on processes involved, among others, in the removal of
cell fragments which are formed in the course of neuronal
degeneration.
That ammonia is capable of inducing apoptosis is indicated by the following observation of Buzanska et al. (2000).
Exposure of glioma cells to ammonia induces apoptotic cell
death by a complex mechanism that involves at least three
195
signalling molecules, NO, protein kinase C and transcription

factor NFkappaB. Inhibition of NO synthase reduced the
number of apoptotic cells, giving evidence to the mentioned
role of inducible NO synthase in programmed cell death.
Using a mouse model of chronic hyperammonemia,
(sparse fur mice with congenital ornithine carbamoyltransferase (E.C.2.1.3.3) deficiency, which show metabolic
aberrations comparable to those observed in the human disease), a widespread cholinergic cell loss was identified by
quantitation of muscarinic M1 binding sites (Butterworth,
1998a,b), which resembled the losses of cholinergic neurones in brains of AD patients (Davies and Maloney, 1976;
McGeer et al., 1984).
8. Astrocytosis is a common morphological aberration

of Alzheimers disease and hyperammonemia
In brains of AD patients, and patients with HE, as well
as after sustained hyperammonemia in experimental animals, astrocytes undergo typical morphological changes.
Ammonia-induced astroglial dysfunctions have been reviewed by Norenberg (1987, 1998), and Frederickson
(1992) summarised observations, which support the idea
that reactive astrocytosis mediates neuropathological events
of AD, including the facilitation of extracellular amyloid
depositions.
Astrocytosis is accompanied by astroglial dysfunction
that is indicated by altered enzyme activities. Ammonia
causes upregulation of astroglial peripheral benzodiazepine
receptors (Butterworth, 2000b), in association with an increased formation of neurosteroids (Norenberg, 1998). Neurosteroids have potent positive modulatory effects on the
neuronal GABA A receptor. In addition, ammonia increases
GABA release and diminishes GABA uptake (Bender and
Norenberg, 2000). GABA receptor dysfunction combined
with ammonia-induced defective astroglial GABA uptake
is presumed to result in an enhanced GABAergic tone. Possible consequences of the amplification of the GABAergic
tone are sustained inhibitory functions, as well as increased
excitation through disinhibition (Roberts, 1976).
An increased tone of GABAergic systems was suggested to play a role in aged brain, and particularly
in AD. It was postulated that an increased tone of the
benzodiazepineGABAergic system interferes with antero
and retrograde axonal transport, caused by the chronic
depolarising block of the pre-terminal axon varicosities
of ascending cholinergic and aminergic neuronal systems.
These are known to be indispensable for normal metabolic
and trophic glianeuron relationships. Their blockade is
presumed to lead to deafferentation of neocortical neuronal
systems (Marczynski (1995).
Benzodiazepine binding sites, as determined by [11 C]
flumazenil positron emission tomography (PET) appear to
be preserved in AD brains, but flumazenil transport rate is
decreased (Meyer et al., 1995; Ohyama et al., 1999). In
196
contrast, a highly significant increase in peripheral benzodiazepine binding sites was found in the frontal and temporal cortex, using [3 H] PK 11195 as ligand (Diorio et al.,
1991). It is now generally accepted that increased expression
of peripheral benzodiazepine binding sites in the brains of
AD patients is mainly associated with microgliosis (Groom
et al., 1995). In agreement with this notion interleukin 1
(IL-1) injections activated forebrain microglia and astrocytes, it induced NO production, and enhanced the release of
glutamate and GABA from the ipsilateral cortex (Casamenti
et al., 1999). Microglia, but not astrocyte activation disappeared within 30 days after IL-1 administration. These
findings support the idea of a dysfunction of the GABAergic
system in AD, which resembles that caused by ammonia in
astrocytes.
Both, in the brains of AD patients (Adolfsson et al., 1980;
Jossan et al., 1991), and in brains of cirrhotic patients with
HE (Rao et al., 1993) MAO B expression is enhanced.
A potential role in ammonia formation by MAO-catalysed
reactions has been discussed in the previous section. An
over-expression of MAO A in hyperammonemic states (Rao
et al., 1993; Mousseau et al., 1997) was also found in AD
brains, however, its increase is not as marked as that of MAO
B (Sherif et al., 1992).
The previously discussed decreased GS activity in AD
brains (Smith et al., 1991; Le Prince et al., 1995) is also
observed in rats with portacaval shunts (Butterworth et al.,
1988) a model of HE.
9. Cerebral glucose utilisation and energy

metabolism are reduced in Alzheimers disease
and in hyperammonemic states
One of the most conspicuous consequences of experimental and disease-related hyperammonemic states is the reduced utilisation of oxygen and glucose, and a decrease in
energy metabolism (Lockwood et al., 1991a; Butterworth,
2000a; Hazell and Butterworth, 1999). At the same time, the
rate by which ammonia is taken up by the brain is enhanced
(Lockwood et al., 1991b). Since in several [31 P] NMR spectroscopic studies no decrease in the level of high energy
phosphates was found it was presumed that the decreased
energy demand is due to a reduced neuronal activity.
In AD brain cerebral blood flow is diminished in the
frontal, temporal, parietal and occipital cortex (Ohyama
et al., 1999). Cerebral oxygen consumption. appears normal
in early onset AD, but is significantly reduced in late onset
AD (Frackowiak et al., 1981).
A reduction in glucose uptake and metabolism in AD
brains (Heiss et al., 1991; Mielke et al., 1992; Bottomley et al., 1992; Meneilly and Hill, 1993; Hoyer, 1993;
Meier-Ruge et al., 1994), as well as a decrease in the density of glucose transporters (Simpson et al., 1994) has been
documented. Overall, cerebral glucose utilisation may be reduced by up to 50%, most prominently in the parietal cortex
(McGeer et al., 1984; Fukuyama et al., 1991), in agreement

with histological abnormalities (Foster et al., 1984). Since
glucose is the major energy source of the brain, and in addition is a precursor of GABA and glutamate, dysfunction
of glucose metabolism has necessarily profound pathophysiologic consequences. Using [31 P] NMR spectroscopy, Pettegrew et al. (1997) observed changes in phosphocreatine
and ADP concentrations, which were considered to indicate
changes in oxidative metabolic rates, and basic defects in
membrane metabolism in AD brain. A decreased rate of oxidative glucose metabolism in favour of glycolysis in AD (as
well as in vascular dementia) is suggested by the increased
levels of pyruvate and lactate in CSF (Parnetti et al., 2000).
Insulin receptors regulate neuronal glucose metabolism.
Therefore, a prominent role of these receptors in the aetiology of AD was postulated (Hoyer et al., 1996). This idea is
supported by the reduced density of neuronal insulin receptors in AD brains (Frlich et al., 1999). The effect of chronically elevated brain ammonia concentrations on neuronal
glucose receptors is not known at present.
In addition to reduced glucose uptake, other parts of the
energy generating machinery are compromised as well, both
in AD and in hyperammonemic states. For example, the expression of mitochondrial cytochrome oxidase gene is lower
in AD than in age-matched controls (Parker, 1991; Simonian and Hyman, 1993; Chandrasekaran et al., 1994). Likewise in synaptosomal mitochondria from brains of sparse fur
mice (the previously mentioned hereditary animal model of
chronic hyperammonemia) the activity of several enzymes of
the electron transport chain is significantly reduced (Qureshi
et al., 1998). These deficits may compromise the formation
of high energy phosphates.
It is beyond the scope of this review to discuss the numerous possible consequences of a decreased availability of
energy in brain function. It should only be mentioned that
the published work demonstrates that membrane functions
and ion movements by ATPases are severely compromised.
10. Ammonia and glutamate

An obvious consequence of the limited availability
of ATP is the impairment of ammonia detoxification by
GS-catalysed formation of glutamine (Fig. 2). This, together
with the changes in neuronal populations, is expected to
result in changed amino acid patterns of brain, CSF and
plasma. Unfortunately, the results of glutamic acid determinations, and of some other amino acids in AD patients are
contradictory. Both, elevations and reductions of glutamate
concentrations have been reported for all three compartments (Klunk et al., 1992; Carney et al., 1991; Martinez
et al., 1993; Jimenez-Jimenez et al., 1998; Pomara et al.
(1992); Kuiper et al., 2000; Basun et al., 1990; Miulli
et al., 1993). Therefore, amino acid determinations were
of little use in the assessment of the importance of extracellular glutamate. It should be mentioned, however, that
CSF glutamine was reported to correlate with cognitive and

memory functions (Basun et al., 1990), which indicates the
importance of the capacity of the brain to form glutamine
for normal function.
Elevated extracellular levels of glutamate have been found
in the CSF, and by brain dialysis of rats with portal systemic
shunts (Therrien and Butterworth, 1991; Tossman et al.,
1987).
In astrocytes exposed to ammonia, the expression of glutamate transporter protein (GLAST) and mRNA was reduced
by 43 and 32%, respectively, and aspartate uptake was reduced by 57% (Chan et al., 2000). A decreased expression of
glutamate transporter proteins was also reported for a transgenic mouse model of AD (Masliah et al., 2000). In conjunction with the previously discussed decrease of GS activity,
the reduction of astrocytic glutamate uptake not only boosts
197
the impairment of ammonia detoxification, but compromises

at the same time the trafficking of glutamate between neurones and astrocytes (Fig. 2). Furthermore, it enhances the
extracellular glutamate concentrations, and thus favours excitotoxic mechanisms. As has been mentioned, cognitive,
emotional and motor symptoms of HE resemble those of
AD. Therefore, not surprisingly basal ganglia dysfunctions
due to a disturbance of glutamatergic and GABAergic neurotransmission are presumed to explain deficits in brain function of HE patients (Weissenborn and Kolbe, 1998).
Recently, several papers appeared reporting alterations
in the expression of glutamate receptor subunits in AD
brains (Carlson et al., 1993; Wakabayashi et al., 1999), but
irrespective of these observations, and based on different
considerations, several authors (Maragos et al., 1987; Frederickson, 1992; Lawlor and Davis, 1992; Harkny et al.,
Fig. 6. Scheme describing possible consequences of chronic hyperammonemia, presumed to lead to progressive impairment of astrocytes and neuronal
damage by excitotoxic mechanisms.
198
2000; Yamada, 2000) had assigned glutamate-induced neuronal degeneration as a pathogenetic mechanism of AD. The
involvement of glutamate-induced excitotoxic mechanisms,
and the degeneration of glutamatergic neurones in the aetiology of AD is especially attractive, because glutamate
is the almost exclusive excitatory, (and GABA the major
inhibitory) neurotransmitter of all cortical structures, and
glutamatergic processes are an established feature of hippocampal memory functions. Hence, defective glutamatergic neuronal networks are able to explain major symptoms
of cortical disconnections (e.g. motor and sensory aphasia)
and memory dysfunctions of AD patients (Advokat and
Pellegrin, 1992; Myhrer, 1998).
From the observations that have been discussed in the
preceding sections a scenario evolves, which is shown in
Fig. 6. The impairment of ammonia detoxification, and
the enhanced formation of ammonia are considered to be
key events. These may be caused by a variety of factors,
e.g. excessive formation of oxygen radicals, formation of
-amyloid deposits, impairment of glucose utilisation, impairment of astrocyte function by exogenous toxins, etc.
Ammonia is not necessarily a primary factor. It may, however, contribute in multiple ways to the symptomatology
and progression of AD. Moderately increased ammonia
levels may initiate positive feed-back mechanisms, resulting in progressive astrocytosis, a decrease in the ability of
the brain to form glutamine, and enhanced accumulation
of ammonia. This in turn could impair energy metabolism
and synaptic function further. As a result, brain damage
and memory deficits would then develop gradually and
progressively via vicious circles.
on the progression of AD is modest. Only younger subjects

(less than 61 years) appear to exhibit a significantly slower
decline in some cognitive functions due to the treatment.
Administration of l-carnitine or acetyl-l-carnitine protects against ammonia toxicity (OConnor et al., 1984;
Matsuoka and Igisu, 1993), restores high energy phosphate
and acetylCoA levels, and reinstates the compromised electron transport chain in brains of experimental animals in
chronic hyperammonemia (Ratnakumari et al., 1993; Rao
et al., 1997; Qureshi et al., 1998). In addition, there is evidence to suggest that l-carnitine prevents glutamate-evoked
excitotoxicity. This effect is mediated by activation of
metabotropic glutamate receptors (Felipo et al., 1994,
1998), and supports the previously discussed excitotoxic
properties of ammonia.
The multiple actions of acetyl-l-carnitine do not allow one
to identify a specific therapeutic target for this compound.
However, the fact that it prevents ammonia toxicity and has
a therapeutic effect on early onset AD reinforces the notion
that ammonia intoxication and AD have some metabolic and
functional aberrations in common.
In view of the complex pathology of AD it may not be
surprising that acetyl-l-carnitine did not produce dramatic
therapeutic effects, although it appears to have effects on several disease-related pathologic aberrations. In order to prevent ammonia toxicity in experimental animals high doses
of acetyl-l-carnitine (or l-carnitine) are needed, which are
not matched in clinical trials. This is probably one of the
reasons for the modest improvements observed.
12. Potential consequences of enhanced brain

tryptophan metabolism
11. Acetyl-l-carnitine, ammonia and
Alzheimers disease
Acetyl-l-carnitine was originally considered of potential
use in AD, because it can serve as precursor of acetylcholine.
But since it is involved in the shuttle of long chain fatty
acids between cytosol and mitochondria, it supports energy
production by facilitating -oxidation of fatty acids. In addition it has numerous other effects. For instance, it modulates
phospholipid metabolism, it affects synaptic morphology
and transmission of multiple neurotransmitters (Pettegrew
et al., 2000), and it protects against neurotoxicity evoked by
mitochondrial uncoupling (Virmani et al., 1995). In agreement with these effects the normalisation of high energy
phosphate levels was observed in acetyl-l-carnitine-treated
AD patients (Pettegrew et al., 1995). The decreased activity of carnitine O-acetyltransferase (EC 2.3.1.8) in AD brain
(Kalaaria and Harik, 1992) was further inducement for the
use of acetyl-l-carnitine therapy in AD.
Long-term clinical trials with acetyl-l-carnitine began
nearly 20 years ago (Acierno, 1983) and were continued
up to date (Brooks et al., 1998; Thal et al., 2000). It is now
evident that the effect of acetyl-l-carnitine administration
Quinolinic acid is an agonist of NMDA receptors, and an

excitotoxic agent, similar to glutamate (Foster and Schwarcz,
1989; Jhamandas et al., 1994). Its formation from tryptophan
is shown in Fig. 7. An intermediary product of this pathway
is kynurenine, another neurotoxic compound.
The enhanced uptake and turnover of tryptophan has been
considered to be a pathogenetic factor of HE (Record, 1991),
and compromised serotoninergic neurotransmission is believed to explain altered sleep patterns in patients with HE
(Butterworth, 1998a,b). Since in the absence of any derangement of liver function hyperammonemia also causes an increase in tryptophan uptake by the brain (Bachmann and
Colombo, 1983) it is generally believed that the observed
derangement of tryptophan metabolism in HE is due to the
elevation of ammonia concentrations. In Fig. 8, steps which
may contribute to quinolinic acid-induced excitotoxicity in
hyperammonemic states are summarised. The validity of
this scheme is supported by the fact that in sparse fur mice
(animal model of hereditary ornithine carbamoyltransferase
deficiency) evidence was found for elevated quinolinic acid
concentrations. Excitotoxic mechanisms induced by quinolinic acid, and mediated by NMDA receptors, were made
199
Fig. 7. Major steps of serotonin, quinolinic acid and kynurenic acid formation from tryptophan.
responsible for the neuronal losses and astrocytosis in sparse

fur mice. (Robinson et al., 1995; Hopkins and Oster-Granite,
1998).
In addition to HE, quinolinic acid attracted some interest as a potential pathogenetic metabolite in AD. However,
in contrast with hyperammonemic states, neither tryptophan
(Storga et al., 1996; Fekkes et al., 1998) nor quinolinic
acid concentrations (Moroni et al., 1986; Sofic et al., 1989)
were found to be significantly elevated in cortical structures
of AD brains. However, it was demonstrated that tryptophan metabolism is enhanced in AD due to induction of
tryptophans-2,3-dioxygenase (E.C.1.13.11.12), the enzyme
which catalyses the formation of N-formylkynurenine from
tryptophan. The rate of tryptrophan metabolism is usually

determined by the kynurenine/tryptophan ratio. This ratio
was found to be correlated with a reduced cognitive performance of the AD patients (Widner et al., 2000). Since it also
correlated with immune markers (neopterin, interleukin-2 receptor and tumour necrosis factor receptor) it is likely that:
(a) enhanced tryptophan degradation to neurotoxic metabolites is due to immune activation and
(b) enhanced tryptophan degradation contributes to the
pathology of AD.
Without intending to stretch the arguments too much in
favour of a potential role of ammonia in AD, it should
200
Fig. 8. Scheme, illustrating possible consequences of sustained hyperammonemia on neurotoxic events elicited by tryptophan metabolites.
nevertheless be noted that kynurenic acid, a metabolite of

kynurenine (Fig. 7 ) is a neuroprotectant (Boegman et al.,
1985; Jhamandas et al., 1994). It has been shown that its
formation from kynurenine is dose-dependently inhibited by
ammonia (Saran et al., 1998). In other words, elevated ammonia concentrations may impair the transformation of the
neurotoxic kynurenine into a neuroprotective agent, and thus
increase kynurenine and quinolinic acid toxicity.
Finally, it should be mentioned that the impairment
of lysosomal proteolysis by tryptophan and kynurenine
(Grinde, 1989) is another likely consequence of chronically
elevated brain ammonia concentrations, as is indicated in
Fig. 8.
13. Lysosomes, -amyloid precursor protein and
ammonia
The molecular biology of -APP, its role in amyloid
plaque formation, and its relation to the development of cognitive and memory dysfunction was a central theme of AD
research of the last two decades (Haass, 1998). Opinions
concerning the importance of lysosomes in the processing
of -APP have repeatedly changed in the past. Nixon et al.
(1992, 2000) reviewed the results of several years work on
the involvement of the lysosomal system of neurones in AD.
According to these reviews, activation of the neuronal lysosomal system, as well as activation of endocytosis and autophagy are prominent features of brain pathology in AD,
and it is believed that during ageing and AD progressive
alterations of lysosomal functions importantly contribute to

the neurodegenerative process.
The following observations illustrate how -APP is internalised from the cell surface, and targeted to lysosomes,
where an array of potential amyloidogenic carboxyl-terminal
fragments is generated. At the same time a potential role of
ammonia in these processes becomes apparent.
(a) -APP was localised in lysosomes (Benowitz et al., 1989;
Kawai et al., 1992).
(b) The degradation, but not the secretion of -APP was
impaired by inhibitors of lysosomal function (ammonia,
chloroquine) (Cole et al., 1989; Caporaso et al., 1992).
(c) It was shown that secretase cleaved -APP at a single site
within the -amyloid region, and generated one secreted
derivative, and one non-amyloidogenic carboxyl-terminal
fragment. In contrast, a complex set of carboxyl-terminal
derivatives was produced by the endosomal-lysosomal
system, including potential amyloidogenic forms. Exposure of the cells to 50 mM ammonium chloride reduced
the entire set of carboxyl-terminal derivatives, and almost
abolished the two largest forms. At the same time ammonia augmented the cell content of full length -APP.
However, ammonia had no effect on secretase cleavage.
(Golde et al., 1992).
Ammonia and methylamine are endogenous lysosomotropic agents (Seglen, 1983). Due to the low
intra-lysosomal pH these bases accumulate within the lysosomes, and cause an increase of the intra-lysosomal pH.
As a consequence, the hydrolysis rate of proteins (Amenta
et al., 1978), glycosaminoglycans (Glimelius et al., 1977)

and of other substrates of lysosomal enzymes is affected.
Usually hydrolysis rates decrease in the presence of ammonia, but enhanced hydrolysis rates are also known,
e.g. the proteolysis of MAP-2, a protein controlling together with Tau protein the polymerisation of microtubules
(Felipo et al., 1993). Ammonia is also known to inhibit
phagosomelysosome fusion in macrophages (Gordon et al.,
1980), and, as has briefly been mentioned earlier, ammonia
affects (among others) the phagocytic activity and capacity
of immortalised microglia cell lines (Atanassov et al., 1994,
1995). In states of sustained hyperammonemia the gradual
accumulation of certain proteins, is to be expected from the
previously mentioned observations.
Microglia are a major source of lysosomal enzymes. The
invasion of microglia into cortical areas, which exhibited
pre-mortem reduced glucose utilisation has been demonstrated by post-mortem determination of -glucuronidase
(E.C.3.2.1.31), a typical lysosomal enzyme (McGeer
et al., 1989). Ammonia is known to increase the activity
(Atanassov et al., 1994), and the release (Tsuboi et al., 1993;
Leoni and Dean, 1983) of lysosomal enzymes from cells. In
agreement with these facts, different classes of lysosomal
enzymes have been localised in extra-lysosomal compartments, for instance in the perikarya and proximal dendrites
of many cortical neurones, and in senile plaques (Cataldo
et al., 1991; Kanamura et al., 1991; Nakamura et al., 1991).
Depending on the stimulus, ammonia enhances or decreases the concentration of various cytokines in microglia
(Atanassov et al., 1994, 1995). Hence, modulation of microglial cytokine release by ammonia may affect a whole
array of cell functions. For example, it is known that IL-1
activates glial NO formation, and glutamate and GABA release (Casamenti et al., 1999). One may speculate, therefore that ammonia accentuates IL-1-induced excitotoxicity.
More relevant to the present considerations is the following example: The inflammatory and chemotactic cytokine
IL-8 is known to cause the release of lysosomal enzymes
(Mukaida et al., 1992). The release of IL-8 from microglia
is increased by ammonia (Atanassov et al., 1995). Thus, ammonia can be expected to be involved at several levels of
cellular metabolism, which affect changes in the ability of
lysosomal enzymes to perform their physiological function.
14. Conclusions
Nine years have elapsed since an ammonia hypothesis of
AD was first published (Seiler, 1993). During this time no
new direct evidence has been reported in favour of a role
of elevated brain ammonia concentrations in the pathology of AD, with one exception. A higher expression of
AMP-deaminase in AD brains was observed (Sims et al.,
1998). This finding indicates the existence of a pathologically elevated source of ammonia within the brain of AD
patients. On the other hand, indirect evidence in favour of a
201
pathogenetic role of ammonia in AD has considerably improved concomitant with our knowledge of consequences of
elevated ammonia concentrations. Several observations on
AD brains were made in recent years, which are analogous
to ammonia-induced alterations of brain metabolism and
function. Admittedly, the new arguments do not improve
decisively the evidence in favour of the ammonia hypothesis
of AD, because the strongest argument available, namely
the excessive formation of ammonia within the brains of
AD patients, and its release into the periphery (Hoyer et al.,
1990) is known since a decade, but has not been further
pursued (Hoyer, 1994).
Ammonia is without doubt an important endogenous neurotoxin, which at concentrations moderately above physiological levels has a number of striking effects on the major neuronal systems, and on numerous metabolic processes,
some of which have been discussed in this review in conjunction with aetiologic and pathologic aspects of AD. Since
AD is slowly progressing, even a minor derangement of ammonia metabolism in brain may create (most probably together with other factors) serious brain pathology via positive feed-back mechanisms, as is indicated in Fig. 6. In view
of these possibilities, it is astonishing that ammonia has attracted so little interest.
As has been already stated, ammonia is presumably not a
primary cause of AD, but it may be involved in the generation of the symptomatology and progression of AD. Consequences predicted from elevated brain ammonia concentrations have implications in several of the currently favoured
hypotheses on the aetiology of AD, such as formation of
amyloid deposits, excitotoxic neuronal damage, astrocyte
dysfunction, impairment of glucose metabolism, impairment
of microglia functions, and of the lysosomal processing of
proteins. These hints should be sufficiently encouraging to
perform experiments with the aim to prove or disprove the
ammonia hypothesis of AD.
The value of a hypothesis is measured by the experiments
that can be designed to evaluate its validity, and by the predictions that it allows to be deduced. Strong arguments in
favour of implications of ammonia in the symptomatology
and progression of AD can only be expected from clinical trials, which are directed towards the removal of excessive ammonia from the patients organism, or which prevent known
ammonia-induced dysfunctions of the brain by methods that
are applied, or are currently explored, in the therapy of
HE and other hyperammonemic states (Butterworth, 2000a;
Seiler, 2000). Among these synergistically acting combinations of centrally acting drugs, such as blockers of glutamate receptor mediated ion channels and acetyl-l-carnitine
with methods capable of improving urea formation, are of
especial interest in this regard.
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Neurochemistry International 41 (2002) 189207

Ammonia and Alzheimers disease

1. Alzheimers disease is a multifactorial disease

Both, dominantly inherited familial (early onset), and late

N. Seiler / Neurochemistry International 41 (2002) 189207

N. Seiler / Neurochemistry International 41 (2002) 189207

(Leonardi et al., 1985). Following a dysfunction of the

2. Ammonia is elevated in blood and brain of

N. Seiler / Neurochemistry International 41 (2002) 189207

conclude that in addition to an age-related impairment of

3. In Alzheimers disease brain ammonia

Ammonia is a normal metabolite of all tissues. In addition,

N. Seiler / Neurochemistry International 41 (2002) 189207

cumulate to unusually high concentrations within neurones.

4. Is ammonia formation enhanced in brains of

Fig. 3. Exogenous and endogenous sources of ammonia in the vertebrate brain.

N. Seiler / Neurochemistry International 41 (2002) 189207

Fig. 4. AMP-deaminase catalysed formation of ammonia.

Fig. 5. Reaction of MAO with a substrate, and radical formation from

1990; Jossan et al., 1991). MAO B deaminates oxidatively

5. Manifestations of ammonia toxicity in brain exhibit

originates from studies of HE, a major neuropsychiatric

6. Ammonia impairs intellectual performance

N. Seiler / Neurochemistry International 41 (2002) 189207

and inhibitory (GABA, glycine) neuronal systems, and to

7. Ammonia and neuronal degeneration

signalling molecules, NO, protein kinase C and transcription

8. Astrocytosis is a common morphological aberration

N. Seiler / Neurochemistry International 41 (2002) 189207

9. Cerebral glucose utilisation and energy

(McGeer et al., 1984; Fukuyama et al., 1991), in agreement

10. Ammonia and glutamate

N. Seiler / Neurochemistry International 41 (2002) 189207

CSF glutamine was reported to correlate with cognitive and

the impairment of ammonia detoxification, but compromises

N. Seiler / Neurochemistry International 41 (2002) 189207

on the progression of AD is modest. Only younger subjects

12. Potential consequences of enhanced brain

Quinolinic acid is an agonist of NMDA receptors, and an

N. Seiler / Neurochemistry International 41 (2002) 189207

responsible for the neuronal losses and astrocytosis in sparse

tryptophan. The rate of tryptrophan metabolism is usually

N. Seiler / Neurochemistry International 41 (2002) 189207

nevertheless be noted that kynurenic acid, a metabolite of

alterations of lysosomal functions importantly contribute to

N. Seiler / Neurochemistry International 41 (2002) 189207

et al., 1978), glycosaminoglycans (Glimelius et al., 1977)

N. Seiler / Neurochemistry International 41 (2002) 189207

N. Seiler / Neurochemistry International 41 (2002) 189207

Gahtan, E., Overmier, J.B., 1999. Inflammatory pathogenesis in

N. Seiler / Neurochemistry International 41 (2002) 189207

Hocking, L.B., Breitner, J.C., 1995. Cumulative risk of Alzheimer-like

Kvamme, E., 1983. Ammonia metabolism in the CNS. Prog. Neurobiol.

N. Seiler / Neurochemistry International 41 (2002) 189207

coupling systems in the cerebral frontal cortex in Alzheimer disease.

N. Seiler / Neurochemistry International 41 (2002) 189207

Ratnakumari, L., Qureshi, I.A., Butterworth, R.F., 1993. Effect of

N. Seiler / Neurochemistry International 41 (2002) 189207

Yankner, B.A., 1996. Mechanisms of neuronal degeneration in

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