Seiler Ammonia and Alzheimer's Disease

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Neurochemistry International 41 (2002) 189–207

Review

Ammonia and Alzheimer’s disease

Nikolaus Seiler∗

Laboratory of Nutritional Oncology, Institut de Recherche Contre les Cancers de l’Appareil Digestif (IRCAD), Strasbourg, France

Abstract

Alzheimer’s 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 thebrain. 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 naturalmodulator 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: Alzheimer’s disease; Blood–brain barrier; Hepatic encephalopathy; Cerebrospinal fluid

1. Alzheimer’s disease is a multifactorial disease

with a complex aetiology

Alzheimer’s disease (AD) (senile dementia of the

Alzheimer type) is the most common neurodegenerative

disorder, accounting for about 70% of all cases of senile

dementia. Five–ten percent of people over the age of 60,

and 20–40% 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, adeno-

sine 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 l’Hôpital, 67091

Strasbourg Cedex, France. Tel.: +33-3-88-119030; fax: +33-3-88-119097.

E-mail address: [email protected] (N. Seiler).

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

onset AD are clinically characterised by the gradual impair-

ment 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), as-

sociated with reactive or fibrous astrocytes (Frederickson,

1992). Activation of microglia is a result of brain inflamma-

tory processes (McGeer and McGeer, 1998; Popovic et al.,

1998; Gahtan and Overmier, 1999). Other histopathologi-

cal aberrations include reduction in the density of neuronal

insulin receptors (Hoyer et al., 1996; Frölich et al., 1999),

and of neurotransmitter receptors of various types: mus-

carinic 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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190 N. Seiler / Neurochemistry International 41 (2002) 189–207

serotonin, dopamine, 4-aminobutyric acid (GABA), and glu-

tamate (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 be-tween the degree of dementia and the severity of these patho-

logical 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 bet-

ter 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 dis-

ease 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 ε4 allele of lipoprotein E is a normal polymor-phism (Strittmatter and Roses, 1995), and the discovery of

the polymorphism in the gene encoding 2-macroglobulin,

Fig. 1. A hypothetical sequence of pathogenetic steps of familial forms of Alzheimer’s disease (according to Selkoe, 1999, modified).

a large multifunctional protein that can act as protease in-

hibitor, 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, gen-

eral age-related changes in organ function and metabolism

have to be taken into consideration as contributing fac-

tors. For example brain vulnerability to -APP increases

with age (Geula et al., 1998). The age-related impairment

of blood–brain barrier function is of special importance,

even though it has been shown that it is equally im-

paired in AD and non-demented elderly (Alafuzoff et al.,

1987; Harik and Kalaria, 1991). In patients with ADcombined with multi-infarct dementia blood–brain barrier

damage is more accentuated than in age-matched controls


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N. Seiler / Neurochemistry International 41 (2002) 189–207 191

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

blood–brain barrier, the exposure of the brain to exoge-

nous 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 im-plicated. In addition, endogenous neurotoxins and metabo-

lites 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 alsoconsidered. 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 trans-

duction (Fowler et al., 1992; Joseph et al., 1993; Saitoh

et al., 1993), aberrant phosphoinositide and gangliosidemetabolism, (Shimohama et al., 1993; Svennerholm, 1994)

and membrane dysfunctions (Nitsch et al., 1992; McClure

et al., 1994; Cowburn et al., 1995) have also been dis-

cussed. 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 mes-

sengers (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 aetiol-

ogy and pathogenesis of AD, and indicate a rather complex

multifactorial disease. It is not intended to evaluate the rela-

tive merits of the divergent observations and ideas that have

been published in the course of the years concerning poten-

tial pathogenetic factors of AD. In fact, much of the work

has been widely ignored by the scientific community, or re-

mained 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

nearly ubiquitous in nature, and is the product of several re-

actions, which are active in most cells and organs. Sophisti-

cated 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 im-

portance. It is for this reason that ammonia deserves specialattention in pathologic conditions.

2. Ammonia is elevated in blood and brain of

patients with Alzheimer’s 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 70–113 nmol/ml concentrations of am-

monia have generally been reported. Cerebrospinal fluid

(CSF) and venous blood ammonia concentrations are withinthe same range (20–100 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 sig-

nificantly higher than in 37 age-matched control sub-

jects. 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 notexhibit this wave form. Tri-phasic waves are suggestive of

hepatic encephalopathy (HE).

Branconnier et al. (1986) found 122 ± 80 nmol ammo-

nia/ml plasma in subjects with AD. The normal range in this

study was 12–55 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, deter-

minations of arterio–venous 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±162g ammonia/min kg brain were released. In strik-

ing contrast, the brains of healthy volunteers retained am-

monia from the arterial blood at a rate of 72 ± 7g/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


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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

arterio–venous differences are evidence for pathological am-

monia metabolism in the brains of AD patients. Deficient

astrocytic glutamine formation, or enhanced formation of

ammonia, or both, could contribute to the excessive releaseof ammonia from AD brains.

3. In Alzheimer’s 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 blood–brain 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 adeno-

sine 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 concentra-

tions (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 trans-

formed 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

Fig. 2. ATP-dependent formation of glutamine, and its hydrolysis to glutamate (astrocyte–neuron glutamate trafficking).

particular importance that patients with AD have signifi-

cantly 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 reperfusion—a situation that causes for-mation 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 (1–40)

and amyloid- peptide (25–35) resulted in both the oxida-

tive inactivation of GS due to radical formation and an in-

crease of amyloid- peptide neurotoxicity. In hippocampal

cell cultures, the GS–amyloid- peptide interaction was ac-

companied by fibril formation and partial fragmentation of the peptide (Aksenov et al., 1997). These observations sug-

gest 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 ex-

act source of the CSF GS is unknown. For obvious reasons

the authors of these papers suggested astrocytic origin. Theobservation of Robinson (2000) may, however, hint at neu-

ronal 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 sensi-

tive 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-


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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 Alzheimer’s 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 con-

centrations. Physiological or pathological enhancement of

activity (e.g. electrical stimulation and convulsions) causes

elevated ammonia levels. Hypoxia is also a reason for in-

creased 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 dif-

ferent 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, oxida-

tive deamination of primary amines, and glycine catabolism

via the glycine cleavage system, are well-known endoge-

nous ammonia sources, which contribute to the steady-state

level of brain ammonia (Kvamme, 1983).

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

A considerable amount of ammonia is formed in the gas-

trointestinal tract (by proteolysis, and by bacteria) from

where it can be taken up into the bloodstream. Deficient hep-

atic urea formation is a major cause of pathological accumu-

lation of ammonia in brain. Bacterial urinary tract infections

are another cause of hyperammonemic states. Although am-

monia and glutamine are excretory products, urea formationcannot be substituted by excretion or by alternative detoxifi-

cation mechanisms. Therefore, urea cycle deficits invariably

cause hyperammonemic states with severe pathology.

Up to now only one metabolic source of brain am-

monia 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 1.6–2.4-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 regula-

tion of purine nucleotides. It hydrolyses AMP to inosine

monophosphate and ammonia (Fig. 4). No correlation wasfound between the age of control subjects and AMP deami-

nase 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 impor-

tance 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 in-

crease was even more marked in AD subjects, and has been

related to gliosis (Adolfsson et al., 1980; Nakamura et al.,


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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, tyra-

mine, 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 blood–brain barrier function in AD

patients (Leonardi et al., 1985; Alafuzoff et al., 1987; Harik

and Kalaria, 1991) substrates of MAO B may penetrate intothe 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 consid-

erations 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 Alzheimer’s disease pathology

The excessive release of ammonia from brain, the re-

duced activity of astrocytic GS activity, and the increased

activity of AMP deaminase is direct evidence for an abnor-

mal 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 ele-

vated 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 be-

havioural abnormalities (aphasia);

• impaired blood–brain 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 el-

evation in brain and other organs is primarily due to the

impairment of liver function. Its distribution in brain is dic-

tated 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 pro-

gression and some key histopathologic characteristics, e.g.

amyloid plaques and neurofibrillary tangles are not a char-

acteristic of HE. In view of the common aspects of these

diseases, and the role that is ascribed to ammonia in the ae-tiology 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 calcu-

lated that a two–five-fold increase of ammonia in brain is

sufficient to compromise the major excitatory (glutamate),


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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 learn-

ing in rats (Aguilar et al., 2000). The mechanism, which

underlies these learning deficits involves presumably a re-

duction 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 temporalregions 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 in-

tellectual 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 se-

quellae, which lead to neuronal degeneration in AD brain

are speculative. Inflammatory processes appear to be in-volved, but the steps which lead from the release of inflam-

matory 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 en-

dothelial cells (de la Monte et al., 2000) may not be com-

pulsory, although activation of microglia, the macrophages

of the brain, is in the opinion of several investigators an un-

doubted 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 mi-

croglia, and astroglioma cell lines; it modifies the release

of cytokines and it increases the activity of lysosomal hy-

drolases (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 indi-

cated 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

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 carbamoyl-

transferase (E.C.2.1.3.3) deficiency, which show metabolicaberrations comparable to those observed in the human dis-

ease), a widespread cholinergic cell loss was identified by

quantitation of muscarinic M1 binding sites (Butterworth,

1998a,b), which resembled the losses of cholinergic neu-

rones in brains of AD patients (Davies and Maloney, 1976;

McGeer et al., 1984).

8. Astrocytosis is a common morphological aberration

of Alzheimer’s disease and hyperammonemia

In brains of AD patients, and patients with HE, as well

as after sustained hyperammonemia in experimental ani-mals, astrocytes undergo typical morphological changes.

Ammonia-induced astroglial dysfunctions have been re-

viewed 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 in-

creased formation of neurosteroids (Norenberg, 1998). Neu-rosteroids 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. Pos-

sible 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 sug-

gested to play a role in aged brain, and particularly

in AD. It was postulated that an increased tone of the

benzodiazepine–GABAergic 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 glia–neuron relationships. Their blockade is

presumed to lead to deafferentation of neocortical neuronal

systems (Marczynski (1995).

Benzodiazepine binding sites, as determined by [11C]

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


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contrast, a highly significant increase in peripheral benzo-

diazepine binding sites was found in the frontal and tem-

poral cortex, using [3H] 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 astro-

cytes, 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 dis-

appeared 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. Anover-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 Alzheimer’s diseaseand in hyperammonemic states

One of the most conspicuous consequences of experimen-

tal and disease-related hyperammonemic states is the re-

duced 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 [31P] NMR spec-

troscopic 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; Bottom-

ley et al., 1992; Meneilly and Hill, 1993; Hoyer, 1993;

Meier-Ruge et al., 1994), as well as a decrease in the den-

sity of glucose transporters (Simpson et al., 1994) has been

documented. Overall, cerebral glucose utilisation may be re-

duced 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 ad-

dition is a precursor of GABA and glutamate, dysfunction

of glucose metabolism has necessarily profound pathophys-

iologic consequences. Using [31P] NMR spectroscopy, Pet-

tegrew et al. (1997) observed changes in phosphocreatineand 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 ox-

idative 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 aetiol-

ogy of AD was postulated (Hoyer et al., 1996). This idea is

supported by the reduced density of neuronal insulin recep-

tors in AD brains (Frölich et al., 1999). The effect of chron-

ically 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 ex-

pression of mitochondrial cytochrome oxidase gene is lower

in AD than in age-matched controls (Parker, 1991; Simo-

nian and Hyman, 1993; Chandrasekaran et al., 1994). Like-

wise 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 nu-

merous 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 determi-

nations, and of some other amino acids in AD patients are

contradictory. Both, elevations and reductions of glutamate

concentrations have been reported for all three compart-

ments (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 extra-

cellular glutamate. It should be mentioned, however, that


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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 gluta-

mate transporter protein (GLAST) and mRNA was reduced

by 43 and 32%, respectively, and aspartate uptake was re-

duced by 57% (Chan et al., 2000). A decreased expression of

glutamate transporter proteins was also reported for a trans-

genic mouse model of AD (Masliah et al., 2000). In conjunc-

tion with the previously discussed decrease of GS activity,

the reduction of astrocytic glutamate uptake not only boosts

Fig. 6. Scheme describing possible consequences of chronic hyperammonemia, presumed to lead to progressive impairment of astrocytes and neuronal

damage by excitotoxic mechanisms.

the impairment of ammonia detoxification, but compromises

at the same time the trafficking of glutamate between neu-

rones and astrocytes (Fig. 2). Furthermore, it enhances the

extracellular glutamate concentrations, and thus favours ex-

citotoxic mechanisms. As has been mentioned, cognitive,

emotional and motor symptoms of HE resemble those of

AD. Therefore, not surprisingly basal ganglia dysfunctionsdue to a disturbance of glutamatergic and GABAergic neuro-

transmission are presumed to explain deficits in brain func-

tion 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; Fred-

erickson, 1992; Lawlor and Davis, 1992; Harkány et al.,


10/19


2000; Yamada, 2000) had assigned glutamate-induced neu-

ronal degeneration as a pathogenetic mechanism of AD. The

involvement of glutamate-induced excitotoxic mechanisms,

and the degeneration of glutamatergic neurones in the ae-

tiology of AD is especially attractive, because glutamate

is the almost exclusive excitatory, (and GABA the major

inhibitory) neurotransmitter of all cortical structures, andglutamatergic processes are an established feature of hip-

pocampal memory functions. Hence, defective glutamater-

gic 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, im-pairment of astrocyte function by exogenous toxins, etc.

Ammonia is not necessarily a primary factor. It may, how-

ever, contribute in multiple ways to the symptomatology

and progression of AD. Moderately increased ammonia

levels may initiate positive feed-back mechanisms, result-

ing 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.

11. Acetyl-l-carnitine, ammonia and

Alzheimer’s 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 addi-

tion 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 agree-

ment 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 activ-

ity 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

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 pro-

tects against ammonia toxicity (O’Connor et al., 1984;

Matsuoka and Igisu, 1993), restores high energy phosphate

and acetylCoA levels, and reinstates the compromised elec-tron 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 evi-

dence 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 andfunctional 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 sev-

eral disease-related pathologic aberrations. In order to pre-

vent 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 braintryptophan metabolism

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 be-

lieved to explain altered sleep patterns in patients with HE

(Butterworth, 1998a,b). Since in the absence of any derange-

ment of liver function hyperammonemia also causes an in-

crease 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 quino-

linic acid, and mediated by NMDA receptors, were made


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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 inter-

est 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 trypto-

phan 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 perfor-

mance of the AD patients (Widner et al., 2000). Since it also

correlated with immune markers (neopterin, interleukin-2 re-

ceptor and tumour necrosis factor receptor) it is likely that:

(a) enhanced tryptophan degradation to neurotoxic metabo-

lites 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


12/19


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 am-

monia concentrations may impair the transformation of theneurotoxic 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 cog-

nitive 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 lyso-

somal system, as well as activation of endocytosis and au-

tophagy 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 in-

ternalised 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. Expo-sure 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 am-

monia 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 lyso-

somotropic agents (Seglen, 1983). Due to the low

intra-lysosomal pH these bases accumulate within the lyso-

somes, and cause an increase of the intra-lysosomal pH.

As a consequence, the hydrolysis rate of proteins (Amenta


13/19


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 am-

monia, but enhanced hydrolysis rates are also known,

e.g. the proteolysis of MAP-2, a protein controlling to-

gether with Tau protein the polymerisation of microtubules

(Felipo et al., 1993). Ammonia is also known to inhibitphagosome–lysosome 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 demon-

strated 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 compart-

ments, 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 de-

creases the concentration of various cytokines in microglia

(Atanassov et al., 1994, 1995). Hence, modulation of mi-

croglial cytokine release by ammonia may affect a whole

array of cell functions. For example, it is known that IL-1activates glial NO formation, and glutamate and GABA re-

lease (Casamenti et al., 1999). One may speculate, there-

fore that ammonia accentuates IL-1-induced excitotoxicity.

More relevant to the present considerations is the follow-

ing 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, am-

monia 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 pathol-

ogy 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 patholog-

ically elevated source of ammonia within the brain of AD

patients. On the other hand, indirect evidence in favour of a

pathogenetic role of ammonia in AD has considerably im-

proved 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 hypothesisof 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 neu-

rotoxin, which at concentrations moderately above physio-

logical levels has a number of striking effects on the ma-

jor neuronal systems, and on numerous metabolic processes,

some of which have been discussed in this review in con-

junction with aetiologic and pathologic aspects of AD. Since

AD is slowly progressing, even a minor derangement of am-

monia metabolism in brain may create (most probably to-gether with other factors) serious brain pathology via posi-

tive feed-back mechanisms, as is indicated in Fig. 6. In view

of these possibilities, it is astonishing that ammonia has at-

tracted so little interest.

As has been already stated, ammonia is presumably not a

primary cause of AD, but it may be involved in the genera-

tion of the symptomatology and progression of AD. Conse-

quences predicted from elevated brain ammonia concentra-

tions 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, impairmentof 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 pre-

dictions 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 tri-

als, which are directed towards the removal of excessive am-

monia 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 combina-

tions of centrally acting drugs, such as blockers of gluta-

mate 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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