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Transcript of Glutamato x Alzheimer
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Adverse psychological impact, glutamatergic dysfunction, and risk factorsfor Alzheimers disease
Trond Myhrer*
Norwegian Defence Research Establishment, Division for Environmental Toxicology, PO Box 25, N-2007 Kjeller, N orway
Received 11 May 1998; accepted 11 May 1998
Abstract
Alzheimers disease (AD) is a neurodegenerative disorder characterized by cell loss and pathological changes in neuronal transmission. In
particular, malfunction in glutamatergic activity may be associated with the impairment of memory seen in Alzheimer patients. Bothhypoactivation and hyperactivation of glutamatergic systems seem to cause impeded cognitive processing in animals. Rats subjected to
rearing in isolation display reduced levels of glutamate in temporal regions accompanied by impaired learning and memory. Similar
cognitive deficits are also seen in animals exposed to behavioral stress. Stress appears to have deleterious effects on cognition caused by
glutamate neurotoxicity leading to attenuated synaptic activity. It is suggested that stress may represent a potential risk factor for AD. The
known risk factors for AD (age, heredity, head trauma, low education, depression) may all be related to glutamatergic dysfunction. Some
difficulties with pharmacological approaches based on glutamatergic agonists are discussed. It is suggested that optimal glutamate-mediated
neurotransmission throughout life may prevent the occurrence of mental decline associated with AD. 1998 Elsevier Science Ltd. All rights
reserved.
Keywords: Alzheimers disease; Risk factors; Glutamate; Over- and under-stimulation; Cognitive impairment; Stress
1. Introduction
Alzheimers disease (AD) is a fatal neurodegenerative
disorder of uncertain etiology. The disease is associated
with changes in behavior, neuroanatomy, and neurochemis-
try. The behavioral changes are seen as progressive, age-
related, chronic cognitive disorders. The neurodegenerative
changes are characterized by the presence of neuritic
plaques, neurofibrillary tangles, and neuronal cell loss.
Pathological changes have been reported to occur in choli-
nergic, glutamatergic, noradrenergic, and serotonergic
systems. However, the pathology of the cholinergic and
glutamatergic systems is the most widely studied.
The purpose of the present review is to show that harmfulpsychological events may have deleterious effects on neuro-
nal transmission in animals, most notably in glutamatergic
systems. Furthermore, attempts are made to relate such find-
ings to the development of AD. Known risk factors for AD
are briefly reviewed, and some new aspects are presented. It
is suggested that environmental factors causing either
hyperactivation or hypoactivity in glutamatergic neuro-
transmission during early life may impair cognitive proces-
sing in later life. All risk factors for AD are related to
glutamatergic dysfunction, and some problems with gluta-
matergic therapeutic intervention are addressed.
2. Known risk factors for AD
The development of AD seems to be associated with
multifactorial causality. The presence of a single risk factor
is only weakly associated with a break out of the disease. It
is the coincidence of several risk factors that will more
certainly cause the onset of AD. The most important risk
factors for AD are age, genetic background, head injury,
lack of education, and, potentially, previous episodes of
depression [37].Age is the most consistent of the risk factors. The inci-
dence rate of the dementias, in general, rises with increasing
age, and may be as high as 25 to 35% in those 85 years old
and over [37]. Regarding the prevalence of AD, the picture
is somewhat blurred, because differences in patterns of diag-
nosis for AD and vascular dementia are seen among nations
[35]. However, the prevalence of AD in Europe has been
reported to be 0.02% for 3059 years; 0.3% for 60
69 years; 3.2% for 7079 years, and 10.8% for 80
89 years [71].
Genetic predisposition plays an important role in the
Neuroscience and Biobehavioral Reviews 23 (1998) 131139PERGAMON
NEUROSCIENCE AND
BIOBEHAVIORAL
REVIEWS
0149-7634/98/$ - see front matter 1998 Elsevier Science Ltd. All rights reserved.PII: S0149-7634(98)00039-6
* Tel.: 47-63-807852; fax: 47-63-807811.
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etiology of AD. The familial form of AD has often a very
early onset (from 40 years of age), but the pathological
processes are similar to those seen in classical AD. The
clinical presentation appears to be identical for these two
forms of AD in spite of different origins. The familial form
of AD is not a single entity, but rather the results from
various genetic defects. One defect has commonly been
related to mutation of a gene on chromosome 21 [89].However, more recent studies also reveal defective genes
on chromosomes 19, 14 and 1 [43,80,81]. Only the gene on
chromosome 19 represents a genetic risk factor for indivi-
duals above 60 years of age in the more common group of
late onset patients. A positive family history of dementia
increases the odds of developing AD at any age by three- to
four-fold [94].
Head injuries of sufficient severity leading to a brief loss
of consciousness or hospitalization can double the risk of
developing AD [55]. As will be seen later, there is biological
plausibility for head trauma as a risk factor for AD. Like-
wise, the sport of boxing represents a risk factor. Repeatedhead trauma in the young adult human can produce early
onset of a dementing process characterized as dementia
pugilistica [64].
Lack of education is a significant risk factor for AD.
When comparing individuals without education to those
with 68 years or more of school, the risk for AD is twice
as high among illiterates [38]. It is assumed that education
has a protective effect because of an increased reserve of
intellectual resources which delay an onset of symptoms by
several years.
More recently a history of depression has been advanced
as a risk factor for AD. Some uncertainty exists as to
whether depressive mood is a very early manifestation of
AD [14]. However, depressive episodes occurring more
than 10 years before onset of dementia symptoms appear
to double the risk of developing AD [86].
3. Psychobiological effects of differential rearing
conditions in animals
In his book of 1949, Hebb proposed the concept of use-
dependent plasticity of the CNS [26]. This concept suggests
the synapse as the critical site of plastic change underlying
learning. The current idea is that memory involves a persis-tent change in communication between neurons, through
biochemical events and structural modifications. Empirical
evidence for this idea has been provided by two experimen-
tal programs during the early 1960s. First, it was demon-
strated by the Rosenzweig group at Berkely that both formal
training and differential environmental conditions caused
measurable changes in neurochemistry and neuroanatomy
of the rat brain [74]. Second, it was reported by Hubel and
Wiesel that occluding one eye of the developing kitten
resulted in reduced number of neurons in the primary visual
cortex [27].
Formal training of rats has been shown to increase their
ability to solve spatial problems and to raise the levels of
acetylcholinesterase (AChE) in the cerebral cortex [40].
Because training in problem-solving is time-consuming
and expensive, it was attempted to provide differential
opportunities for informal learning by rearing animals in
different environments. The standard procedure for different
housing conditions has usually been that newly weaned ratsare assigned to one of three different treatment conditions
for a period of 12 months. Rats reared in an enriched
environment are housed in a colony cage containing differ-
ent objects that are regularly changed to introduce novelty.
Rats reared in a standard or social environment are housed
as a group in a colony cage, but without any objects. Rats
reared in isolation are housed in individual cages without
objects.
Young rats reared in an enriched environment displayed
higher concentrations of AChE in neocortical areas than rats
from social or isolated rearing conditions. These measures
of AChE were seen to correlate positively with learning andmemory and can last throughout the life span [72]. Subse-
quent studies have revealed that similar effects can also be
obtained in rats assigned to differential environments as
adults. However, the neurochemical effects develop some-
what more rapidly in younger than older animals, and the
magnitude of effects is often larger in the younger animals
[73]. Although the initial work on this topic was carried out
with laboratory rats, the effects of differential experience on
the brain have been shown to apply for several strains of
rats, laboratory mice, gerbils, squirrels, and monkeys [72].
Glutamate, rather than acetylcholine, has more recently
been shown to be involved in neuronal transmission impor-
tant for learning and memory. It has also been demonstrated
that glutamatergic systems can be more susceptible to envir-
onmental influence than cholinergic systems. Young rats
were reared in enriched, social or impoverished conditions
for 2 months after weaning. Only glutamatergic activity (as
measured by high-affinity d-aspartate uptake) in the lateral
enthorinal cortex responded to the rearing treatments,
whereas no changes in glutamatergic high-affinity uptake
were recorded in the temporal or frontal cortices. Moreover,
high levels of glutamate uptake in rats reared in an enriched
environment and low levels in rats reared in an isolated
environment correlated significantly with both acquisition
and retention of a visual discrimination task. However, theconcentrations of choline acetyltransferase (ChAT) in fron-
tal, temporal, or enthorinal cortices did not respond to the
rearing conditions [63]. The lack of cholinergic responses,
in contrast to the positive findings of Rosenzweig and co-
workers, may be related to procedural differences in neuro-
chemistry and behavior across studies. However, both regio-
nal and hemispheric differences in the concentrations of
ChAT were seen in the study of Myhrer et al. [63].
For quite some time acetylcholine has been considered as
the very transmitter used by neural systems involved in
learning and memory [13]. However, results from more
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recent studies do not support this early view. The choliner-
gic projection systems from nucleus basalis magnocellularis
to neocortical areas and from the medial septum to the
hippocampal region are probably more conveniently formed
to serve a modulatory function on memory than an informa-
tion storing system per se. It has been suggested that impair-
ment of attentional processes may result from
neurochemical lesions of the nucleus basalis [70]. In arecent review of relevant literature on the role of acetylcho-
line for learning and memory, it is concluded that this role
seems to be overstated, and that cholinergic systems are
more specifically involved in attention/arousal than in
mechanisms underlying learning and memory processes as
such [6].
The corticocortical fiber systems connecting association
areas are assumed to use glutamate as neurotransmitter [19].
This is one reason for considering glutamate as a pivotal
transmitter for learning and memory. Another reason is that
long-term potentiation (LTP), being regarded as a leading
candidate for mechanisms underlying preservation of infor-mation, is associated with enhanced excitatory activity in
glutamate receptors [9]. Both NMDA and AMPA receptors
are involved in LTP. NMDA receptors seem to be required
for induction of LTP, whereas AMPA receptors appear
necessary for the maintenance of LTP [4]. The findings
that cognitive changes following differential rearing are
more closely related to altered levels in glutamate than acet-
ylcholine activity [63] appear tenable with prevalent views
upon the functional activities in which glutamatergic and
cholinergic systems are involved.
Further experimentation has demonstrated that enriched
experience is also able to increase anatomical measures,
such as cortical thickness, neuronal/glial ratio, and size of
synaptic contact areas. Neuroanatomical studies have
reported effects of experience on dendrite branching and
the number of dendritic spines per unit of dendrite [72].
More recently, it has been shown that adult rats exposed
to an enriched spatial environment display increased spine
density on hippocampal CA1 pyramidal cells [56]. It should
be noted, however, that the term enrichment of experi-
ence only denotes more complexity of stimulation than that
of the standard colony environment. The feral environments
in which the species evolved are probably far more complex
and rich of stimulation than the enriched laboratory situa-
tion.
4. Psychobiological effects of behavioral stress in animals
A number of external factors can cause stressful events in
the natural surroundings of animals. Stress reactions are
often associated with overstimulation or great strain,
which implies activation of the sympathetic nervous system.
Brief exposures to stress probably serve an adaptive func-
tion, whereas chronic, long-lasting overstimulation may
lead to harmful effects upon the organism [49].
It is now well established that behavioral stress activates
the hypothalamicpituitaryadrenal axis which results in
enhanced levels of glucocorticoids in the blood stream. As
early as 1969, it was demonstrated that increased concen-
trations of glucocorticoids are toxic to hippocampal neurons
in guinea pigs and rats [97]. Chronic systemic administra-
tion of glucocorticoids can produce hippocampal damage in
both rats [77] and primates [78]. Similarly, chronic restraintstress in rats also produces hippocampal damage. Both
chronic injections of glucocorticoids and behavioral stress
have destructive effects on pyramidal neurons in the CA3
region of rats [95,97]. Likewise, hippocampal degeneration
is also seen in primates having been subjected to sustained
social stress [93]. The regulation of the hypothalamicpitui-
taryadrenal axis is influenced by the aging process. Aged
rats have elevations in basal corticosterone levels [75] and
hypersecrete corticosterone after acute stress [76]. Adrena-
lectomy at midlife attenuates age-related reduction in hippo-
campal neurons [42]. The aging brain seems to be
particularly vulnerable to detrimental effects of glucocorti-coids and stress. On the other hand, chronic stress in young
rats appears to promote the process of aging by causing age-
related hippocampal neurodegenerative changes [95].
Acute stress induced by painful stimulus of formalin
results in marked elevation of glutamate and aspartate in
cortical areas and substantia nigra in rats [65]. Restraint
stress of rats has been reported to increase glutamate uptake
and release in the frontal cortex, hippocampus, and septum,
but not the striatum. This increase of glutamate was evident
after 30 min of stress. Thereafter a plateau was reached after
1 h and was maintained after 4 h of continuous stress [22]. A
20 min restraint procedure has been shown to increase
extracellular glutamate in the prefrontal cortex, hippocam-
pus, striatum, and nucleus accumbens. Increase of aspartate
was also seen in the same regions, with the exception of the
striatum. Quantitative differences in responding across
structures suggest that excitatory amino acids are released
in a regionally selective manner [52]. Exposure to 10 min
repeated tail pinch stress demonstrates that the glutamater-
gic responding in the prefrontal cortex adapts, but a similar
adaptive response is not present in the hippocampus [3]. In
the prefrontal cortex, glutamatergic systems seem to be
profoundly activated by stress. This stress-induced gluta-
mate activation can further increase release of dopamine
in the frontal cortex [32].Glutamatergic responding to stress is of particular inter-
est, because elevated levels of glutamate can yield excito-
toxic effects leading to neuronal death. In a recent study,
acute restraint stress has been shown to cause a modest
increase of glutamate levels in the hippocampus of young
and old rats. After termination of the stress procedure,
hippocampal glutamate concentrations continued to rise in
the aged rats, reaching a level about five times higher than in
the young rats and remained elevated for at least 2 h. A
similar pattern was also seen in the medial prefrontal cortex,
although not that pronounced [45]. Enhanced glutamate
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responses after stress may probably increase the vulnerabil-
ity of the aging brain to neuronal damage. There is evidence
that increased concentrations of corticosterone can elevate
the basal level of glutamate in the hippocampus of rats [87].
It has been suggested that restraint stress could damage CA3
neurons via increased excitation of the dentate granule cells
[95].
The adverse effect of stress on glutamate-mediated neuro-transmission appears to interfere with mechanisms for
learning and memory. Rats exposed to restraint stress and
tail shock display impaired LTP and enhanced long-term
depression (LTD) in the hippocampal CA1 region. Such
effects on LTP and LTD are prevented by the administration
of NMDA receptor antagonists, suggesting that the effect of
stress is mediated through the activation of the NMDA
subtype of glutamate receptors [39]. This finding is in
good agreement with the cognitive dysfunctions seen
following stress. Exposure to chronic psychosocial stress
in rats results in impaired spatial memory, whereas artificial
elevation of corticosterone levels only mildly affects spatialperformance [41]. Chronic restraint stress results in a tran-
sient impairment of acquisition and performance in an
eight-arm radial maze. It is suggested that hippocampal
dysfunction is involved in the cognitive deficit, since this
structure is critical for spatial functions [46]. Similar cogni-
tive deficits are observed in old rats in a water maze. More-
over, compared with young rats, aged rats had higher basal
levels of hippocampal corticosterone, and the cognitive defi-
ciencies among aged rats were related to loss of hippocam-
pal neurons [31]. However, the hippocampal region is
probably not the sole structure compromised during aging.
In a study based on comparisons with the effects of circum-
scribed brain lesions, it was concluded that age-related
dysfunctions occur in subdivisions of the prefrontal cortex
as well as the hippocampus [100].
There is a considerable loss of neurons in hippocampal
subfields CA1 and CA3 in aged rats. However, postnatal
handling appears to prevent or reduce the increase of adre-
nal secretion seen in later life. Of particular interest is the
finding of attenuated hippocampal cell loss and better water
maze performance among handled rats [50]. Furthermore,
environmental enrichment in adulthood, like neonatal hand-
ling, can have the potential to protect the aging hippocam-
pus from glucocorticoid neurotoxicity [53].
5. Glutamatergic dysfunctions in animals modeling
stages leading to AD
As seen from the previous sections, rearing in an impo-
verished environment can lead to reduced activity in both
glutamatergic and cholinergic neurons, and behavioral
stress can cause increased activity in glutamatergic systems.
These experimental approaches apparently seem to have
opposite effects on glutamate-mediated neurotransmission,
but may in the long run result in similar impairments of
cognitive functions. Isolation of young animals caused
reduced development of synaptic contacts, because fewer
nerve terminals using glutamate or acetylcholine are
recorded. Stress caused glutamatergic excitotoxic effects
leading to loss of already established synapses and neurons.
Both procedures result in neural states mimicking those seen
in AD.
Glutamatergic systems are evidently compromised in ADand can be related to many of the neurochemical and cogni-
tive deficits associated with the disease. Glutamatergic
neurotransmission in neocortical regions and hippocampus
is severely disrupted [24,47,66]. Corticocortical association
fibers arising from presumably glutamatergic pyramidal
cells appear to be disconnected in AD. The decreased levels
of glutamate in Alzheimer brains observed by some inves-
tigators may be the results of disrupted connections [47].
Also, cholinergic deficits are seen in AD in terms of reduced
levels of ChAT in neocortical areas along with extensive
loss of cells in the nucleus basalis of Meynert [67].
It is well established that excitatory amino acids have theDr Jekyll and Mr Hyde properties of stimulating neurons for
beneficial purposes or stimulating them to death when
mechanisms for controlling such stimulation fail [64]. Initial
experimentation with kainic acid and other analogues of
glutamate (termed excitotoxins) showed that they are
toxic, because they can cause excess activation of glutamate
receptors resulting in prolonged depolarization, neuronal
swelling, and ultimate cell death [83]. Such neural reactions
are also seen to follow head trauma in animals. Brain injury
induced by fluid percussion in rats causes endogenous gluta-
mate and aspartate to leak out of cells and accumulate in the
extracellular compartment where they can exert excitotoxic
action at external membrane receptors [16]. The rise in
amino acid concentrations may result from neuronal
discharge, rupture of neurons and bleeding. Following
damage to the spinal cord in rats much of the increase in
the levels of excitatory amino acids comes from electrical
activity of neurons [44].
Insufficient blood supply has been demonstrated to
produce excitatory damage. Transient cerebral ischemia in
rats results in marked elevation of extracellular glutamate
and aspartate in the hippocampus [5]. Studies of brain tissue
from animals surviving a period of temporary ischemia/
hypoxia show regional differences in vulnerability. The
hippocampus is among the most vulnerable regions in therat, and within this structure the subfield CA1 is more easily
damaged than the CA3 area [15]. Both global and focal
ischemia in rats and monkeys produce marked hippocampal
lesions accompanied by memory deficits. However, this
ischemia-induced mnemonic impairment is probably also
associated with extrahippocampal damage not readily
detectable with conventional histological methods [2].
Interestingly, chronic cerebrovascular insufficiency for 1
9 weeks in rats has been proposed as an aging model
mimicking neuropathology and memory dysfunction asso-
ciated with AD [12].
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Some mixed findings have been made with regard to
alterations in glutamate levels and release in aged rodents.
In several studies of rats, age-related decreases have been
reported, whereas increases have been seen in mice [29].
However, reduced density of the NMDA receptor in the
hippocampus and neocortex of senescent rats has been
found [7,29,92]. This finding suggests that glutamatergic
neurotransmission is impaired with aging and may beinvolved in the cognitive decline seen in old rats.
A glutamatergic denervation model of AD has been
proposed for the rat [59]. Lesions of the temporal cortex,
the lateral entorhinal cortex, or the fiber connections
between these structures impair visual memory. In particu-
lar, the fiber transections cause marked retrograde amnesia
and a somewhat weaker anterograde amnesia [57,58]. A
number of the disrupted axons use glutamate as neurotrans-
mitter, because reduced high-affinity d-aspartate uptake is
seen in the denervated structures [60]. It appears likely that
glutamate is involved in the mnemonic processing in the
temporal region, since systemic administration of glutama-tergic agonists can completely restore the memory function
in rats with lesion-induced amnesia [61].
Experimental manipulations or natural processes (aging)
can cause glutamatergic dysfunctions modeling correspond-
ing states in AD. AD-related states can be produced by
isolation, stress, head trauma, vascular deficits, glutamater-
gic denervation or aging. This assembly of compromising
factors should permit the derivation of testable hypotheses.
For instance, rearing in isolation combined with stress, head
trauma, and/or glutamatergic denervation in adult life may
impair cognitive performances in a cumulative way in adult
or aged rats. Such paradigms might be useful in testing
models for interactions and/or accumulation of risk factors
for AD.
6. Risk factors for AD and glutamate-mediated
neurotransmission
The known risk factors for AD (age, genetics, head
trauma, low education, depression) and the novel factor of
stress suggested in this study do not seem to have much in
common. Apparently, these factors represent a rather wide
variety of domains. However, all factors may in some way
be related to the function of the transmitter glutamate. Therelationship may appear particularly relevant in view of
selective degeneration in AD of structures that receive
glutamatergic innervation [25]. This finding raises the possi-
bilities that excitotoxic processes or poorly developed
cognitive functions may be associated with reduced capa-
city in glutamatergic systems.
The results from animal research presented in this study
show that behavioral stress can cause excitotoxic damage in
glutamate-mediated neuronal systems. Corresponding
studies based on human subject do not seem to exist.
Reports about AD and stress focus on the caregivers of
Alzheimer patients [48]. The process of validating the
hypothesis of stress as potential risk factor for AD might
encounter methodological problems, because stress can
hardly be objectively defined for humans. Unlike episodes
of depression, which may be related to hospitalization or
psychiatric counseling, quantification of episodes of stress is
not readily attainable. Some individuals may experience a
particular situation as stressful, whereas others do not. Theresponses are linked to the process of coping. Some are
better provided with personality traits to cope with stress-
ful events than others. For this reason, it does not appear
meaningful to operate with objectively defined stressors.
A possible way to circumvent this problem may be to relate
long-lasting episodes of life crisis to prevalence of AD.
In high age, the vulnerability to vascular pathology seems
to increase considerably, and AD and vascular dementia are
not easily differentiated. Ischemia/hypoxia may produce
glutamatergic excitotoxicity and cell death in areas critical
for memory processing. This is seen in both global and focal
ischemia in animals which result in damage in the temporalregion accompanied by mnemonic dysfunctions. Similar
results are also observed in humans following episodes of
transient global or focal ischemia [2]. If humans, like
animals, are more vulnerable to stress in old age, the elderly
may react more readily with neurotoxicity to stressful
events. In addition to the possibility of critical neuronal
reactions in old age, other risk factors may accumulate
with the elapse of time.
On chromosome 19, the gene ApoE4 which encodes for
apolipoprotein E, has been associated with increased risk for
AD [79,91]. However, apolipoprotein E which transports
cholesterol, is also associated with vascular pathology.
ApoE4 may predispose for silent myocardial ischemia,
because individuals with the E4 allele have higher total
plasma cholesterol levels and higher low-density lipoprotein
cholesterol levels [36]. The prevalence of both overt coron-
ary artery disease and silent myocardial ischemia increases
with age [18]. Furthermore, the frequency of ApoE4 has
been reported to be higher not only in AD, but also in
patients with vascular dementia [30]. The ApoE4 allele
appears as a factor elevating plasma cholesterol and further
accelerating the development of atherosclerosis [85]. These
findings suggest that genetically caused AD may not
exclude the involvement of vascular mechanisms. Focal
brain ischemia can lead to release of extracellular glutamateresulting in excitotoxicity and neuronal death. It has also
been shown that synthesis and release of apolipoprotein E
and clusterin may be regulated by a glutamatergic NMDA
mechanism [51]. The latter study provides a possible
mechanistic linkage between glutamate-mediated neuro-
transmission and the genetic risk factor (ApoE4) for AD.
Whereas the relationship between head trauma and gluta-
mate-induced excitotoxicity appears evident, changes in
glutamatergic activity are not evidently associated with
episodes of depression. Perturbations in plasma concentra-
tions of glutamate in patients with major depression have
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been reported [1]. In depression, there is evidence for regio-
nal alterations in cortical neurons either as a result of the
disease or its treatment [68]. However, elevated levels of
cortisol have been observed both during stress and depres-
sion [90]. Related mechanisms seem to be activated by
stress and depression, suggesting that episodes of depression
may have deleterious effects on glutamatergic systems.
The risk of developing AD has been reported to beincreased in individuals with either low education or low
lifetime occupational attainment [54,88]. The prevalence of
AD is markedly increased among illiterates compared with
persons with formal education [99]. It has been suggested
that educational and occupational achievement could result
in increased synaptic density in neocortical association
areas because of increased stimulation [38]. Since learning
and memory rely heavily on neural systems using glutamate
as their transmitter, poorly developed or maintained cogni-
tive activities may be accompanied by reduced function in
glutamatergic systems.
7. Glutamatergic malfunction in AD and therapeutic
intervention
The cholinergic hypothesis of AD has existed for quite
some time (197677), whereas an hypothesis related to
glutamatergic transmission is of more recent origin
[24,47]. The cholinergic involvement in AD has been firmly
established. Reduced levels of ChAT in neocortical areas
have been seen along with extensive cell loss in the nucleus
basalis of Meynert. The cholinergic dysfunction has been
reported to correlate with the severity of dementia in AD
[66]. Glutamatergic dysfunction is also evidently involved
in the pathophysiology of AD, and can be related to many of
the neurochemical and cognitive deficits associated with
this disease. Glutamatergic neurotransmission in neocortical
areas and the hippocampus is severely compromised
[24,47,66]. Both the cholinergic and glutamatergic hypoth-
eses have led to attempts to apply therapeutical strategies.
Numerous clinical trials have been made with cholinergic
therapies, and the cholinesterase inhibitor tacrine seems to
be the most promising one. However, this agent yields only
modest mnemonic improvement in patients with moderate
symptoms only and has some adverse side effects [96]. As
previously stressed in this study, cholinergic systems aremore involved in arousal than learning and memory per se
[6]. Thus, cholinergic therapy may have some limited
effects in AD by supporting attentional aspects of memoriz-
ing. An alternative approach represents clinical trials with
glutamatergic agonists, provided they do not cause neuro-
toxic damage.
The glutamatergic partial agonist d-cycloserine which
acts at the glycine site of the NMDA receptor, may appear
as an appropriate candidate. Cycloserine has about 60% of
the maximal response of glycine [28]. We have observed a
weak positive effect of d-cycloserine on declarative
memory in a small number of Alzheimer patients [20].
However, in an extensive study ofd-cycloserine no bene-
ficial effects were seen on explicit memory in patients with
AD [17], but an improvement of implicit memory in patients
with AD has been reported to follow administration of d-
cycloserine [82]. The relatively modest effects obtained by
the glutamatergic agonist may be related to the deteriorated
state of the neuronal systems using glutamate as their trans-mitter in AD. d-Cycloserine has been demonstrated to
produce restoration of memory function in humans pre-trea-
ted with scopolamine [34] and in rats subjected to denerva-
tions of glutamatergic fibers in the temporal region [62].
The very first signs of neuropathology in AD are detected
in the transentorhinal cortex. Then a step-wise spread is seen
to encroach upon the neighboring structures, the entorhinal
and temporal cortices and finally the hippocampus [8].
These areas are vital for formation of memory and are
most likely connected with glutamatergic systems [21]. In
a recent neuropathological study of AD, it was shown that in
patients with the mildest clinically detectable dementia thenumber of neurons in layer II of the entorhinal cortex was
decreased by 60%. In patients with severe dementia the
corresponding decrease was 90% [23]. These findings may
question whether remaining glutamatergic systems in criti-
cal temporal areas are sufficiently preserved to profit
adequately from treatment with glutamatergic agonists. If
administration of agonists may stimulate glutamate-
mediated transmission effectively enough to retard the
devastating process of AD, early detection of the disease
would be of great benefit. Such early detection before symp-
toms become manifest has been reported to be possible [33].
Pharmacological treatment of the cognitive deficits in AD
may require a combination therapy. It has been reported
that, in addition to hypoactivity of glutamatergic cortical
pyramidal neurons and reduced excitatory cholinergic
stimulation of these cortical neurons, a major inhibitory
influence on pyramidal neurons by serotonergic and
GABAergic neurons appears to be preserved in AD [21].
Thus, not only administration of glutamatergic and choli-
nergic agonist would be beneficial, but perhaps also the use
of seretonergic and GABAergic antagonists. It has recently
been shown that nicotine combined with d-cycloserine
synergistically enhance spatial navigation in aged rats [69].
8. Concluding remarks
The development of AD may be related to genetic and
environmental factors. Among the latter factors, adverse
psychological impact may play an important role in the
pathogenesis. Understimulation may result in impaired
development of glutamate-mediated transmission. Oversti-
mulation may produce glutamate neurotoxicity and neuro-
nal death. Both hypoactivity and hyperactivity in
glutamatergic systems probably lead to similar effects on
the organism, namely a reduced reservoir of synaptic
T. Myhrer / Neuroscience and Biobehavioral Reviews 23 (1998) 131139136
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contacts supporting cognitive functions. Episodes of severe
stress during life may cause a number of microlesions, lead-
ing to reduced redundancy in glutamatergic systems in old
age.
It is well documented that behavioral stress impairs the
ability to acquire and retain new information in animals.
Both cognitive, emotional, and motivational deficits are
seen to follow when animals cannot cope with a stressfulsituation [84]. Marked memory impairment has been
demonstrated in combat veterans with posttraumatic stress
disorder compared with soldiers without the stress
syndrome [98]. Glutamate dysfunctions are probably
involved in the nervous substrates governing the above defi-
cits.
Glutamate neurotoxicity appears to be involved in a
number of diseases in the central nervous system. Such
toxicity can exacerbate acute injury to the CNS due to
prolonged seizures, compromised blood supply, glucose
deprivation, and mechanical trauma. Glutamate neurotoxi-
city may also be a factor in chronic degenerative disorderslike Parkinsons disease and Huntingtons disease [10]. The
link between excitatory amino acids and AD is further
strengthened by the finding that cultured human neurons
exposed to increased extracellular concentrations of gluta-
mate and aspartate can stimulate the production of paired
helical filaments resembling those that form neurofibrillary
tangles in AD [11].
A growing body of data corroborates the notion that
harmful psychological effects can produce glutamatergic
dysfunctions in animals. However, modest efforts seem to
have been put in qualitative analyses of psychobiological
effects. For instance, episodes of impoverished environ-
ment, both during rearing and later in life, may model
both educational and occupational shortcomings in humans.
Furthermore, psychobiological effects of repeated episodes
of stress and effects of the length of each exposure time may
elucidate the potential for stress as a risk factor for the
development of AD.
Provided the views advanced in this study are valid, it
appears that optimal activity in glutamate-mediated neuro-
transmission during life will make individuals less vulner-
able to age-related cognitive decrement associated with AD.
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