Alzheimer's disease (AD) is a progressive, degenerative form of
dementia of unknown etiology and without effective treatment. It is estimated
that around 10% of the population in the Western world, over 65 years of age,
is affected. Clinical features include memory loss, personality changes,
decline of cognitive functions; there are no diagnostic tests, clinical or
paraclinical, except neuropathology, to affirm the diagnosis which remains one
of exclusion. Although etiologically Alzheimer's disease may be a heterogenous
disease, the hallmark of the disease are the neuropathological changes
characterised by neurofibrillary tangles and senile amyloid plaques seen in
brain tissues on autopsy. Recent studies suggest that Alzheimer's disease may
in fact be a systemic disease (Etcheberrigaray et al., 1993; Jabbour et al.,
1992; Joachim et al., 1989).
Patients with Down syndrome over the age of 40 years have been found
to have invariable premature development of characteristic AD neuropathological
changes (Cork, 1990). There is however no absolute correlation between the
pathological changes and the clinical manifestations of dementia (Olson and
Shaw, 1969; Wisniewski and Rabe, 1986). Over the age of 40, some 15-51% of
patients with Down syndrome develop dementia, conflicting reports result from
problems associated with assessing dementia in mentally retarded patients
(Cork, 1990; Zigman et al., 1987).
In addition to these clinical and neuropathological similarities
(Ikeda et al., 1989), there are both genetic and biochemical data to suggest
some common disease mechanisms. It has been suggested that nondisj unction of
chromosome 21 may underlie both disorders (Potter, 1991). Amyloid beta (A4)
precursor protein is encoded by a gene found on chromosome 21 and it is
expressed in the brain (Goldgaber et al., 1987; Robakis et al., 1987; Tanzi et
al., 1988). Some point mutation of APP have been described in familial cases of
early-onset Alzheimer's disease (Goate et al., 1991). Furthermore, the
possibility that the gene for at least some familial Alzheimer disease may be
found on chromosome 21 has been suggested (Steele et al., 1989). Increased
incidence of Alzheimer's disease have been reported in mothers of patients with
Down syndrome (Schupf et al., 1994).
Biochemical similarities include: (1) similar neurotransmitter
deficits: cholinergic, serotonin and adrenergic (Cork, 1990; Mann et al., 1985;
McGeer et al., 1984; Sacks and Smith. 1989); (2) microtubule assembly defects
(Khatoon and Iqbal, 1989; Krawczun et al., 1990; Matsuyama and Jarvik, 1989);
(3) reduced levels of biopterin (Kay et al., 1986); (4) elevation of brain
interleukin 1 and S100 im-munoreactivity (Griffin et al., 1989; Jorgensen et
al., 1990); (5) reduction of D(3H) aspartate binding (Simpson et al., 1989);
(6) loss of cortical glutaminergic neurons (Reynolds and Godridge, 1985;
Reynolds and Warner, 1988), (7) elevation of brain aluminium (Edwardson and
Candy, 1989; Farrar et al.. 1990).
In this study we expanded a preliminary report on eight patients with
Alzheimer's disease demonstrating excessive in vitro glutamine toxicity
(Peeters et al., 1992). We conducted the present study to test the hypothesis
that a common metabolic defect could be found in Alzheimer's disease patients
with or without Down syndrome.
2. Material and methods
Peripheral blood samples were cultured for 72 hours in TC199 medium
(Seromed), supplemented with 25% human AB serum, phytohaemagglutinine C (IBF
France), penicillin and streptomycin. Culture technique, harvesting and
microscopic examination were carried out according to standard, previously
described methods (Peeters and Lejeune, 1989).
The following products were added on initiation of culture (all
products were Sigma products unless otherwise specified); the entire panel
could not always be performed for each patient: (1) inosine (INO): 125 mg/l;
(2) alanosine (ALA): 0.0625 mg/l. kindly provided for by the Laboratory of
Biochemical Pharmacology (National Institute of Health, Bethesda, Maryland,
USA); (3) azaserine (AZA): 0.0156 mg/l; (4) adenosine (ADE): 16 mg/l; (5)
cytidine (CYT): 6.25 mg/l; (6) guanosine (GUA): 3.1 mg/l; (7) putrescine (PUT):
6.25 mg/l; (8) methotrexate (MET): 1.2 X 10-8 M; (9) glutamine
(GLN): 95 mg/l; (10) uridine (URI): 3.1 mg/l; (11) HAT medium: 62.5 µM
hypoxanthine; 0.25 µM aminopterin; 10 µM thymidine.
The following products were added 12-16 h prior to termination of the
culture: (12) mycophenolic acid (MYC): 0.6 X 10-6 M; (13)
theophylline (THE): 750 mg/l; (14) rT3: 5 mg/l.
The lymphocytes cultures were harvested with standard techniques used
for chromosomal analysis. Slides were stained with Giemsa and coded. A minimum
of 2500 cells were read to calculate the mitotic index, expressed as the ratio
of mitosis over the total number of nuclei. Each patient was compared to itself
and paired t-tests were performed on the differences.
Percentage increment or decrease of mitotic index in patients with Alzheimer's
disease compared to normal controls. Abbreviations: rT3: reverse
triiodothyronine; MYC: mycophenolic acid; 23D: 2,3-diphosphoglycerate; GLN:
glutamine: INO: inosine; ALA: L-alanosine; AZA: azaserine; ADE adenosine; THE:
theophylline; HAT: HAT medium; URI: uridine; CYT: cytidine; GUA: guanosine;
PUT: putrescine; MET: methotrexate. For each group of patients tested, the
first horizontal line indicates the number of patients who were tested with a
given product; the second line gives the name of the product which was added to
the culture; the third line indicates the mean percentage increment or decrease
of the mitotic index; on the fourth line, the value of the standard deviation
is indicated. STUD: Student's t-test (two-tailed). * Student's Mest > 2, p
<0.05; **o Student's t-test > 2.8, p < 0.01*** Student's t-test >
3.8, p < 0.001
Sixteen patients with Down syndrome and a regressive Alzheimer type
dementia were studied (only 14 had glutamine added to their lymphocyte
cultures). There were 4 men and 12 women in this study with a mean age of 44.8
years (range 20-53 years). Hypothyroidism was excluded in all these patients.
Patients suffered from progessive loss of cognitive skills, desorientation,
neurological degradation (functional decline in areas such as orientation,
memory, verbal and motor skills and self-care abilities) and loss of sphincter
control. A therapeutic trial of folic acid and of vitamine B12 therapy was
ineffective. Controls used for analysis were 171 patients with Down syndrome
without dementia (59 of whom had glutamine added to their lymphocyte culture).
All the patients with Down syndrome had documented trisomy 21 on chromosomal
analysis. Results were also compared to 156 normal controls (74 of whom had
glutamine added to their lymphocyte cultures). Normal controls were healthy
volonteers (85 patients) or parents of a miscarriage referred to the genetics
laboratory who on chromosomal analysis had a normal caryotype (71
Nineteen patients with the clinical diagnosis of advanced
Alzheimer's disease were studied (16 of whom had glutamine added to their
lymphocyte culture). There were 5 men and 14 women; mean age at the time of
this study 77 years (range 46-97 years). Diagnostic criteria were the following
(McKhann et al., 1986): dementia as evidenced by clinical examination
documented in most patients by the "mini-mental state" (Folstein et al., 1975)
(MMS score ranged from 0/30 to 19/30); deficits in two or more areas of
cognition; progressive deterioration in specific cognitive functions such as
language (aphasia), motor skills (apraxia) and perception (agnosia); impaired
acitivities of daily living; the absence of documented underlying neurological,
psychiatric or systemic pathology (thyroid and hematological diseases were
exclude); a brain scan which was normal for age. There were 156 normal control
patients of whom 26 age-matched control patients aged more than 60 years and 11
patients over 70 years were examined with the same method. In the age-matched
control group, ten patients presented dementia of known etiology (head trauma,
vascular disease, etc.). Patients with Alzheimer's disease and age-matched
controls were on the same hospital ward and received the same diet, they had
good nutrition status and were not given any protein supplementation. All
patients received medication: antidepressants and/or neuroleptic medications
which had been interrupted at least 12 hours prior to blood sampling for this
investigation. Other controls used were 156 normal controls and 171 patients
with Down syndrome without Alzheimer's type dementia.
Percentage increment or decrease of mitotic index in patients witn Alzheimer's
disease compared to normal age-matched controls. Abbreviations as in Fig.
2.2. Statistical analysis
Results were analyzed by comparing the mitotic index of each
experiment (each additif) to the patient's own control culture and were
expressed as the percentage incre ment or decrease in mitotic index.
Statistical comparison between groups were based on the Student's Mest (two
tailed test). Given the complexity of the metabolic path ways which were
examined, we only analyzed result which were significant at a p value of less
3.1. Patients with Alzheimer's disease
When patients with Alzheimer's disease were compared to normal
controls, there was a highly significant difference (p < 0.001) in the in
vitro toxicity to glutamine (Fig 1). The same in vitro toxicity was observed
when age matched controls were analyzed (Fig. 2).
It is of interest to note that 9 normal controls (14%) mean age 38.4
years, decreased their mitotic index in the presence of glutamine (more than
15% decrease in the mitotic index). When controls of more than 70 years of age
were examined 4/11 demonstrated in vitro toxicity to glutamine, two of whom
were demented (but thought not to have Alzheimer's disease). No age-related
differences were observed between controls aged less than 70 years and those
aged more than 70 years.
When Alzheimer disease patients were compared to normal controls who
also demonstrated in vitro sensitivity to glutamine no differences in reaction
to different additives were observed. However significant differences in
reactions were noted (in the presence ofinosine(p < 0.01), adenosine (p <
0.001) and guanosine (p < 0.01) when all patients were examined (normal
controls and patients with Alzheimer's disease) based on their different
sensitivity to exogenous glutamine (Fig. 3).
Percentage increment or decrease of mitotic index in patients (normal controls
and patients with Alzheimer's disease) with different sensitivity to exogenous
glutamine (increase over 0% or decrease of more than 15%). Abbreviations as in
3.2. Down syndrome patients
When patients with Down syndrome and Alzheimer type dementia were
compared to Down syndrome patients without dementia (Fig. 4) or to normal
controls, a highly significant difference (p< 0.001) in glutamine toxicity
In vitro toxicity to glutamine was frequently observed in Down
syndrome controls. Fourty-seven percent of DS aged more than twenty years
showed in vitro toxicity to glutamine.
When the metabolic patterns between Down syndrome patients who
increased their mitotic index in the presence of glutamine was compared to
those who demonstrated toxicity (control patients with Down syndrome and those
manifesting Alzheimer type dementia) there were significant differences as
shown in Fig. 5.
Fig. 4. Percentage increment or decrease of
mitotic index in patients with Down syndrome with or without Alzheimer type
dementia. Abbreviations as in Fig. 1.
Fig. 5. Percentage increment or decrease of mitotic index in
patients with Down syndrome (with or without dementia) and different
sensitivity to exogenous glutamine (increase over 0% or decrease of more than
15%). Abbreviations as in Fig. 1.
3.3. Comparison between Alzheimer's disease patients and
Down syndrome demented patients
There was no highly significant difference observed in the in vitro
response to different additives between patients with Alzheimer's disease and
those with Down syndrome suffering from dementia (Fig. 6).
3.4. Comparison between normal controls and patients with
No differences in the different reactions to various metabolites
were observed between normal controls and patients with Down syndrome (results
Our findings suggest that both patients with Alzheimer's disease and
Down syndrome patients suffering from dementia have excessive in vitro
lymphocyte toxcicity to glutamine. In the presence of exogenous glutamine there
is a highly significant decrease in the mitotic index in lymphocyte cultures.
There was no difference in the toxic response to glutamine observed between
patients suffering from Alzheimer's disease and Down syndrome patients
suffering from dementia.
Although glutamine is not neurotoxic it converts to glutamate (Huang
et al., 1994; O' Driscoll et al., 1993; Piani and Fontana, 1994).
Glutamine/glutamate metabolism is complex and regulated by several enzymes,
purine nucleotides and a number of amino acids (Erecinska and Silver, 1990).
Glutamine can produce glutamate not only through the action of
phosphate-activated glutaminase but also through glutamine transaminase. Given
the rapid interchange between glutamine and glutamate, the problems of
compartmentation of the various enzymes intervening in glutamine/glutamate
metabolism in the brain and in other tissues, the fluxes between the
compartments and the fact that this work could not address the precise
concentrations of one or the other, we will use speak of glutamine/glutamate
Glutamate is one of the major excitatory transmitters in the brain.
Fast excitatory transmission in the central nervous system is mediated mainly
by L-glutamate and glutamate receptors are found throughout the mammalian brain
(Hayashi, 1954, Monaghan et al., 1989). Glutamate is released by an estimated
40% of synapses (Fonnum, 1984), The glutamate receptor system is thought to be
involved in the first steps of learning and memory acquisition (Morris, 1989),
as well as neuronal survival and dendritic outgrowth (Jorgensen et al., 1990).
Excess exposure to glutamate can destroy neurons, a process Olney calls
excitotoxicity. Glutamate is toxic to neurons in culture and in vivo; immature
brains are especially susceptible to the toxic effects of glutamate. Various
patterns of brain damage can be observed depending on the developmental stage
in which the neurotoxic process is triggered.
Certain glutamate analogs known to share the neuroexcitatory
properties of glutamate mimic its neurotoxic effects (Olney, 1991) whereas
glutamate antagonists have a neuroprotective effect (Kahn et al., 1993). Recent
experiments implicate the glutamate receptor as a mediator of the toxic effect
of glutamate (Heinemann et al., 1991). At least 7 receptor subunits, different
glutamate receptors are expressed in specific brain regions. It is of interest
that human receptor gene GluR5 has been assigned to chromosome 21 (Potier et
al., 1993) and maps in the vicinity of the gene for familial amyotrophic
lateral sclerosis (Eubanks et al., 1993; Gregor et al., 1993).
The possible link between anomalies in glutamine/glutamate metabolism
and Alzheimer's disease is not new. Glutamate is one of the major excitatory
neurotransmkters in the mammalian brain and has been implicated in the
pathogenesis of acute and chronic neurological diseases by virtue of its
excitotoxic property. It has been proposed that degenerative diseases
(Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis) may
involve neuronal death by excessive activation of the glutamate receptor system
and/or genetic or acquired abnormalities in glutamate sensitivity of certain
neurons (Greenamyre and Young, 1989; Lipton and Rosenberg, 1994; Meldrum and
It has been reported that early in the course of Alzheimer's disease,
there is a decrease in CSF glutamine content (Procter et al., 1988) and lack of
glutaminase activity. Neurochemical changes precede cellular pathology. Later
in the course of the disease, there is anatomical and biochemical evidence
suggesting both pre and post synaptic disruption of glutaminergic pathways
(Cowburn et al., 1988; Hardy et al., 1987). It is known that in Alzheimer's
disease there is severe loss of glutamataminase positive (pyramidal) cortical
neurons as well as loss of glutamate terminals in the hippocampal region
(Akiyama et al., 1989; Cross et al., 1989; McGeer et al., 1989) and of NMDA
receptor (one of the glutamate receptors). Beta amyloid inactivates
oxidation-sensitive glutamine synthetase (Hensley et al., 1994). Recently it
has been suggested that the detection of glutamine synthetase in the
cerebrospinal fluid of Alzheimer's disease patients may be a potential
diagnostic biochemical marker (Gunnersen and Haley, 1992). Glutamine synthetase
plays a key role in converting the neurotransmitter and excitotoxic amino acid
glutamate to the non neurotoxic glutamine. Aluminium which has been found to be
elevated in the brains of patients with Alzheimer's disease disrupts normal
glutamine/glutamate homeostasis (Zielke et al., 1993). These findings all point
to some abnormality in the glutamine/glutamate pathway in Alzheimer's disease
which is further supported by our study.
Patients with Down syndrome have well documented biochemical anomalies
of some of the major regulators of the glutamine/glutamate metabolic pathway as
shown in Table 1. In patients with Down syndrome the dynamic equilibrium among
multiple facilitative and inhibitory factors of glutamine/glutamate metabolism
might create an imbalance rendering the system prone to an expression of
excitotoxicity. It is of interest that, when we compared the in vitro metabolic
responses observed in patients with Down syndrome who increased their mitotic
index in the presence of glutamine to those for whom glutamine was toxic
(decrease in the mitotic index greater than - 15%), other significant
differences appeared. Significant opposite effects in the presence of inosine
(p< 0.001), cytidine (p< 0.01) and guanosine (p< 0.001) were noted. In
Down syndrome patients who demonstrated in vitro toxicity to glutamine. these
nucleotides were also toxic, (whereas they slightly increased mitotic index in
cultures where glutamine was beneficial). This raises the hypothesis that
perhaps underlying imbalances in purine metabolisme may play an important role
in the glutamine toxicity observed in patients with Down syndrome (finding
which is of interest given the role purine metabolites play in
Fig. 6. Percentage increment
or decrease of mitotic index comparing patients with Alzheimer's disease and
Down syndrome demented patients. Abbreviations as in Fig. 1.
Lymphocyte toxicity to glutamine seemed to increase with age. Sixteen
out of 46 (34%) Down syndrome patients aged less than 30 years demonstrated in
vitro glutamine toxicity whereas in those over 30 years 10 out of 17 (58%) Down
syndrome patients demonstrated toxicity. Our findings suggest that patients
with Alzheimer's disease have a primary or secondary defect in glutamine/
glutamate metabolism. Alzheimer' s disease would in fact be a "metabolic
disease" as has already been suggested by other authors (Etcheberrigaray et
al., 1993; Iwatsuji et al., 1989; Joachim et al., 1989). This is supported by
the fact that:
amyloid B protein deposits have been observed in multiple non-neuronal
tissues (Joachim et al., 1989);
a decrease in heat-stable lymphocyte glutamate dehydrogenase activity
has been reported (Iwatsuji et al., 1989);
similar anomalies in actin expression in lymphocytes from patients
with Down syndrome and Alzheimer's disease have been found (Jabbour et al.,
a potassium channel dysfunction in fibroblasts may identify patients
with Alzheimer's disease (Etcheberrigaray et al., 1993).
Our findings would be in keeping with the suggestic that a generalized
metabolic anomaly exists in Alzheimer disease. It is of interest that in our
control sample, age less than 70 years of age, 14% decreased their mitotic
index in the presence of exogenous glutamine. This finding is in keeping with
the incidence of Alzheimer' s disease in the general population. However 30% of
controls over the age of 70 demonstrated in vitro sensitivity to glutamine
suggesting possible dysregulation with increasing age (perhaps also in
relationship with purine imbalances as suggested by the toxicity of inosine,
adenosine and guanosine in the cultures of control patients in which glutamine
was toxic). The increased toxicity of exogenous glutamine t lymphocyte culture
was more frequent and of earlier onse in patients with Down syndrome. Indeed,
in the Down syndrome control group 34% of patients aged less that thirty years
of age decreased their mitotic index more than 20% and excessive in vitro
sensitivity to glutamine was observed in 58% of patients with Down syndrome
over in age of thirty.
We hypothesize that Alzheimer's disease may be du to:
1. a primary genetic or acquired defect of glutamine/ glutamate
2. complex purine and/or amino acid dysregulation responsable for
secondary alterations in glutamine/ glutamate metabolism.
It must be remembered that monosodium glutamate one of the world's
most widely and heavily used for additives. Certain people may be genetically
unable metabolize exogenous glutamine/glutamate and even normal doses will
eventually produce toxic effects. It is interest that in populations where
glutamine/glutamate used frequently as a food additive, one might expected
increased incidence of Alzheimer' s disease. In fact the incidence is lower
than in the West (Treves et al., 1993) This would be in keeping with genetic
metabolic differences. Prolonged exposure to low dose glutamate (due to a
genetic or acquired abnormality of glutamate metabolism or sensitivity of
certain neurons) is as toxic as the acute form of neurotoxicity which causes
neuronal degeneration (Rothstein et al., 1993). If this hypothesis is true, it
has important preventive medical implications. Indeed genetically susceptible
persons should restrict their diet with regards to glutamine/glutamate intake.
In patients in whom purine synthesis dysregulation exists it would be of
importance to examine whether these changes are amendable to modulation as we
suggested in patients with Down syndrome (Peeters et al., 1993). Further
studies are needed both to confirm our findings and to expand this observation
by using glutamate agonists and antagonists. Patients in the early stages of
the disease should also be examined.
Table 1: Documented biochemical anomalies of regulators of
glutamine metabolism in patients with Down syndrome
|Biochemical anomalies||Implications for dysregulation
|Increased gene dosage effect for enzymes intervening in de
novo purine synthesis and for cystathionine B synthetase. Profound derangement
of purine metabolism (Lejeune, 1990; Peeters et al., 1993).||Purine
nucleotides play a major role in modulation of key enzyme glutamine/glutamate
metabolism. ADP (increased in DS) is a ..... inhibitor of glutamine synthetase
(Erecinska and Silver, 1990).
|Anomalies of amino acids: increase in cysteine and lysine,
decrease in serine (Lejeune et al., 1992).||Uptake of glutamine
inhibited by neutral amino acids such as serine and lysine. Cysteine is a
glutamate analog and is a known excitotoxin (Hea... et al., 1990; Olney et al..
1972,1990; Olney. 1991).
|Decreased levels of zinc (Bjorksten et al., 1980; Stabile et
al., 1991).||Zinc is an inhibitory modulator of channel function and
chelanon of zinc cysteine may play a role in cysteine neurotoxicity (Olney,
1991; Steele " al., 1989).
|Derangement of glucose metabolism, frequent
hypoglycemia.||Hypoglycemia associated with release of excitotoxins
(Sandberg ..... 1986).
|Superoxide dismutase assigned chromosome 21 (Sinet et al.,
1974).||Oxidative stress thought to play a role in the pathogenesis of
.....neurodegenerative disorders (Coyle and Puttfarcken. 1993).
|Patients with Down syndrome often have higher than normal
ammonium levels.||Ammonium is thought to play a role in the pathogenesis
of Alzheimer disease (Lai et al., 1989; Simpson et al., 1989).
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