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

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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

T. Myhrer / Neuroscience and Biobehavioral Reviews 23 (1998) 131139132


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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

T. Myhrer / Neuroscience and Biobehavioral Reviews 23 (1998) 131139 133


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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



7/9

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.

References

[1] Altamura C, Maes M, Dai J, Meltzer HY. Plasma concentrations of

excitatory amino acids, serine, glycine, taurine and histidine in major

depression. Eur Neuropsychopharmacol 1995;5(Suppl):7175.

[2] Bachevalier J, Meunier M. Cerebral ischemia: are the memory defi-

cits associated with hippocampal cell loss?. Hippocampus

1996;6:553560.

[3] Bagley J, Moghaddam B. Temporal dynamics of glutamate efflux in

the prefrontal cortex and in the hippocampus following stress: effects

of pretreatment with saline or diazepam. Neurosci 1997;77:6573.

[4] Bekkers JM, Stevens CF. NMDA and non-NMDA receptors are co-

localized at individual excitatory synapses in cultured rat hippocam-

pus. Nature 1989;341:230233.

[5] Benveniste H, Drejer J, Schousboe A, Diemer NH. Elevation of the

extracellular concentration of glutamate and aspartate in the rat

hippocampus during transient cerebral ischemia monitored by intra-

cerebral microdialysis. J Neurochem 1984;43:13691374.

[6] Blokland A. Acetylcholine: a neurotransmitter for learning and

memory?. Brain Res Rev 1996;21:285300.

[7] Bonhaus DW, Perry WB, McNamara JO. Decreased density, but not

number, ofN-methyl-d-aspartate, glycine and phencyclidine binding

sites in hippocampus of senescent rats. Brain Res 1990;532:8286.[8] Braak H, Braak E. Neuropathological stageing of Alzheimer-related

changes. Acta Neuropathol 1991;82:239259.

[9] Brown TH, Chapman PF, Kairiss EW, Keenan CL. Long-term

synaptic potentiation. Science 1988;242:724728.

[10] Choi DW. Glutamate neurotoxicity and diseases of the nervous

system. Neuron 1988;1:623634.

[11] De-Boni U, McLachlan DR. Controlled induction of paired helical

filaments of the Alzheimer type in cultured human neurons, by

glutamate and aspartate. J Neurol Sci 1985;68:105118.

[12] de-la-Torre JC, Fortin T. A chronic physiological rat model of

dementia. Behav Brain Res 1994;63:3540.

[13] Deutsch JA. The cholinergic synapse and the site of memory.

Science 1971;174:788794.

[14] Devanand DP, Sano M, Tang MX, Taylor S, Gurland BJ, Wilder D,

Stern Y, Mayeux R. Depressed mood and incidence of Alzheimersdisease in the elderly living in the community. Arch Genet Psychiat

1996;53:175182.

[15] Diemer NH, Siemkowicz E. Regional neurone damage after cerebral

ischemia in normo- and hypoglycemic rats. Neuropathol Appl

Neurobiol 1981;7:217227.

[16] Faden AI, Demediuk P, Panter SC, Vink R. The role of excitatory

amino acids and NMDA receptors in traumatic brain injury. Science

1989;244:798800.

[17] Fakouhi TD, Jhee SS, Sramek JJ, Benes C, Schwarz P, Hantsburger

G, Herting R, Swabb EA, Cutler NR. Evaluation of cycloserine in

the treatment of Alzheimers disease. J Geriat Psychiat Neurol

1995;8:226230.

[18] Fleg JL, Gerstenblith G, Zonderman AB, Becker LC, Weisfeldt ML,

Costa PT, Lakatta EG. Prevalence and prognostic significance of

exercise-induced silent myocardial ischemia detected by thalliumscintigraphy and electrocardiography in asymptomatic volunteers.

Circulation 1990;81:428436.

[19] Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J

Neurochem 1984;42:111.

[20] Fonnum F, Myhrer T, Paulsen RE, Wangen K, ksengard AR. Role

of glutamate and glutamate receptors in memory function and

Alzheimers disease. N Y Acad Sci 1995;757:475486.

[21] Francis PT, Sims NR, Procter AW, Bowen DM. Cortical pyramidal

neurone loss may cause glutamatergic hypoactivity and cognitive

impairment in Alzheimers disease: investigative and therapeutic

perspectives. J Neurochem 1993;60:15891604.

[22] Gilad GM, Gilad VH, Wyatt RJ, Tizabi Y. Region-selective stress-

induced increase of glutamate uptake and release in rat forebrain.

Brain Res 1990;525:335338.

[23] Gomez-Isla T, Price JL, McKeel Jr DW, Morris JC, Growdon JH,Hyman BT. Profound loss of layer II entorhinal cortex neurons

occurs in very mild Alzheimers disease. J Neurosci

1996;16:44914500.

[24] Greenamyre JT. The role of glutamate in neurotransmission and

neurologic disease. Arch Neurol 1986;43:10581063.

[25] Greenamyre JT, Young AB. Excitatory amino acids and Alzhei-

mers disease. Neurobiol Aging 1989;10:593602.

[26] Hebb DO. Organization of behavior. New York: Wiley, 1949.

[27] Hubel DH, Wiesel TN. Binocular interaction in striate cortex of

kittens reared with artificial squint. J Neurophysiol 1965;28:1041

1059.

[28] Huettner JE. Competitive antagonism of glycine at the N-methyl-d-

aspartate (NMDA) receptor. Biochem Pharmacol 1991;41:916.



8/9

[29] Ingram DK, Garofalo P, Spangler EL, Mantione CR, Odano I,

London ED. Reduced density of NMDA receptors and increased

sensitivity to dizocilpine-induced learning impairment in aged rats.

Brain Res 1992;58:273280.

[30] Isoe K, Urakami K, Sato K, Takahashi K. Apolipoprotein E in

patients with dementia of the Alzheimer type and vascular dementia.

Acta Neurol Scand 1996;93:133137.

[31] Issa AM, Rowe W, Gauthier S, Meaney MJ. Hypothalamicpitui-

taryadrenal activity in aged, cognitively impaired and cognitivelyunimpaired rats. J Neurosci 1990;10:32473254.

[32] Jedema HP, Moghaddam B. Glutamatergic control of dopamine

release during stress in the rat prefrontal cortex. J Neurochem

1994;63:785788.

[33] Jobst KA, Smith AD, Szatmari M, Molyneux A, Esiri MM, King E,

Smith A, Jaskowski A, McDonald B, Wald N. Detection in life of

confirmed Alzheimers disease using a simple measurement of

medial temporal lobe atrophy by computed tomography. Lancet

1992;340:11791183.

[34] Jones RW, Wesnes KA, Kirby J. Effects of NMDA modulation in

scopolamine dementia. Ann N Y Acad Sci 1991;640:241 244.

[35] Jorm AF. The epidemiology of Alzheimers disease and related

disorders. London: Chapman and Hall, 1990.

[36] Katzel LT, Fleg JL, Paidi M, Ragoobarsingh N, Goldberg AP.

ApoE4 polymorphism increases the risk for exercise-induced silentmyocardial ischemia in older men. Arterioscler Thromb

1993;13:14951500.

[37] Katzman R. Clinical and epidemiological aspects of Alzheimers

disease. Clin Neurosci 1993;1:165170.

[38] Katzman R. Education and the prevalence of dementia and Alzhei-

mers disease. Neurology 1993;43:1320.

[39] Kim JJ, Foy MR, Thompson RF. Behavioral stress modifies hippo-

campal platsticity through N-methyl-d-aspartate receptor activation.

Proc Natl Acad Sci USA 1996;93:47504753.

[40] Kretch D, Rosenzweig MR, Bennett EL. Dimensions of discrimina-

tion and level of cholinesterase activity in the cerebral cortex of the

rat. J Comp Physiol Psychol 1956;82:261268.

[41] Krugers HJ, Douma BRK, Andringa G, Bohus B, Korf J, Luiten

PGM. Exposure to chronic psychososial stress and corticosterone

in the rat: effects on spatial discrimination learning and hippocampalprotein kinase Cg immunoreactivity. Hippocampus 1997;7:427

436.

[42] Landfield PW, Baskin RK, Pitler TA. Brain aging correlates: retar-

dation by hormonalpharmacological treatments. Science

1981;214:581584.

[43] Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA,

Weber JL, Bird TD, Schellenberg GD. A familial Alzheimers

disease locus on chromosome 1. Science 1995;269:970973.

[44] Liu D, Thangnipon W, McAdoo DJ. Excitatory amino acids rise to

toxic levels upon impact injury to the rat spinal cord. Brain Res

1991;547:344348.

[45] Lowy MT, Wittenberg L, Yamamoto BK. Effect of acute stress on

hippocampal glutamate levels and spectrin proteolysis in young and

aged rats. J Neurochem 1995;65:268274.

[46] Luine V, Villegas M, Martinez C, McEwen BS. Repeated stresscauses reversible impairments of spatial memory performance.

Brain Res 1994;639:167170.

[47] Maragos WF, Greenamyre JT, Penney JB, Young AB. Glutamate

dysfunction in Alzheimers disease: an hypothesis. TINS

1987;10:6568.

[48] McCarty EF. Caring for a parent with Alzheimers disease: process

of daughter caregiver stress. J Adv Nurs 1996;23:792803.

[49] McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Op

Neurobiol 1995;5:205216.

[50] Meaney MJ, Aitken DH, Bhatagar S, Sapolsky RM. Postnatal hand-

ling attenuates certain neuroendocrine, anatomical, and cognitive

dysfunctions associated with aging in female rats. Neurobiol

Aging 1991;12:3138.

[51] Messmer-Joudrier S, Sagot Y, Mattenberger L, James RW, Kato AC.

Injury-induced synthesis and release of apolipoprotein E and clus-

terin from rat neural cells. Eur J Neurosci 1996;8:2652 2661.

[52] Moghaddam B. Stress preferentially increases extraneuronal levels

of excitatory amino acids in the prefrontal cortex: comparison to

hippocampus and basal ganglia. J Neurochem 1993;60:16501657.

[53] Mohammed AH, Henriksson BG, Soderstrom S, Ebendal T, Olson

T, Seckl JR. Environmental influences on the central nervous system

and their implication for the aging rat. Behav Brain Res1993;57:183191.

[54] Mortel KF, Meyer JS, Herod B, Thornby J. Education and occupa-

tion as risk factors for dementias of the Alzheimer ischemic types.

Dementia 1995;6:5562.

[55] Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB,

Heyman A, Jorm AF, Kokmen E, Kondo K, Rocca WA, et al. Head

trauma as a risk factor for Alzheimers disease: a collaborative re-

analysis of case-control studies. Int J Epidemiol 1991;20(Suppl

2):S2835.

[56] Moser M-B, Trommald M, Andersen P. An increase in dendrite

spine density on hippocampal CA1 pyramidal cells following spatial

learning in adult rats suggests the formation of new synapses. Proc

Natl Acad Sci USA 1994;91:1267312675.

[57] Myhrer T. Retroactive memory of a visual discrimination task in the

rat: role of temporalentorhinal cortices and their connections. ExpBrain Res 1991;84:517524.

[58] Myhrer T. Selective lesions in the temporalhippocampal region of

the rat: effects on acquisition and retention of a visual discrimination

task. Behav Neural Biol 1992;58:815.

[59] Myhrer T. Animal models of Alzheimers disease: glutamatergic

denervation as an alternative approach to cholinergic denervation.

Neurosci Biobehav Rev 1993;17:195202.

[60] Myhrer T, Iversen EG, Fonnum F. Impaired reference memory and

reduced glutamergic activity in rats with temporoentorhinal

connections disrupted. Exp Brain Res 1989;77:499506.

[61] Myhrer T, Paulsen RE. Memory dysfunction following disruption of

glutamergic systems in the temporal region of the rat: effects of

agonistic amino acids. Brain Res 1992;599:345352.

[62] Myhrer T, Paulsen RE. Memory impairment in rats with glutama-

tergic temporal systems disrupted is attenuated by d-cycloserine:effects of postoperative time of injection. Psychobiol

1995;23:233239.

[63] Myhrer T, Utsikt L, Fjelland J, Iversen EG, Fonnum F. Differential

rearing conditions in rats: effects on neurochemistry in neocortical

areas and cognitive behaviors. Brain Res Bull 1992;28:427434.

[64] Olney JW, Farber NB. Excitatory transmitter neurotoxicity and

Alzheimers disease. In: Giacobini E, Becker R, editors. Alzhei-

mers disease: therapeutic strategies. Boston, MA: Birkhauser

1994:2938.

[65] Palkovits M, Lang T, Patthy A, Elekes I. Distribution and stress-

induced increase of glutamate and aspartate levels in discrete brain

nuclei of rats. Brain Res 1986;373:252257.

[66] Palmer AM, Gershon S. Is the neuronal basis of Alzheimers disease

cholinergic or glutamatergic?. FASEB J 1990;4:27452752.

[67] Perry EK. The cholinergic hypothesisten years on. Brit Med Bull1986;42:6369.

[68] Procter AW, Francis PT, Lowe SL, Pangalos MN, Steele JE, Bowen

DM. Clinical correlations of the neurobiological changes of aging.

Ann Med Interne Paris 1990;141(Suppl 1):36.

[69] Riekkinen M, Riekkinen Jr P. Nicotine and d-cycloserine enhance

acquisition of water maze spatial navigation in aged rats. Neurorep

1997;8:699703.

[70] Robbins TW, Everitt BJ, Marston HM, Wilkinson J, Jones GH, Page

KJ. Comparative effects of ibotenic acid- and quisqualic acid-

induced lesions of the substantia innominata on attentional function

in the rat: further implications for the role of cholinergic neurons of

the nucleus basalis in cognitive processes. Behav Brain Res

1989;35:221240.



9/9

[71] Rocca WA, Hofman A, Brayne C, Breteler MM, Clarke M, Cope-

land JR, Dartigues JF, Engedal K, Hagnell O, et al. Frequency and

distribution of Alzheimers disease in Europe: a collaborative study

of 1980 1990 prevalence findings. Ann Neurol 1991;30:381390.

[72] Rosenzweig MR. Experience, memory, and the brain. Am Psychol

1984;39:365376.

[73] Rosenzweig MR, Bennett EL. Psychobiology of plasticity: effects of

training and experience on brain and behavior. Behav Brain Res

1996;78:5765.[74] Rosenzweig MR, Krech D, Bennett EL, Diamond MC. Effects of

environmental complexity and training on brain chemistry and anat-

omy: a replication and extension. J Comp Physiol Psychol

1962;55:429437.

[75] Sapolsky RM. Do glucocorticoid concentrations rise with age in the

rat?. Neurobiol Aging 1991;13:171174.

[76] Sapolsky RM, Krey LC, McEwen BS. Glucocorticoid-sensitive

hippocampal neurons are involved in terminating the adrenocortical

stress response. Proc Natl Acad Sci USA 1984;81:61746177.

[77] Sapolsky RM, Krey LC, McEwen BS. Prolonged glucocorticoid

exposure reduces hippocampal neuron number: implications for

aging. J Neurosci 1985;5:12221227.

[78] Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage

associated with prolonged glucocorticoid exposure in primates. J

Neurosci 1990;10:28972902.[79] Saunders AM, Strittmatter WJ, Schmechel D, St George-Hyslop PH,

Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLa-

chlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD.

Association of apolipoprotein E allele E4 with late-onset familial and

sporadic Alzheimers disease. Neurology 1993;43:14671472.

[80] Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L,

Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, Potter

H, Heston LL, Martin GM. Genetic linkage evidence for a familial

Alzheimers disease locus on chromosome 14. Science

1992;258:668671.

[81] Schellenberg GD, Boehnke M, Wijsman EM, Moore DK, Martin

GM, Bird TD. Genetic association and linkage analysis of the apoli-

poprotein CII locus and familial Alzheimers disease. Ann Neurol

1992;31:223227.

[82] Schwartz BL, Hashtroudi S, Herting RL, Schwartz P, Deutsch SI. d-Cycloserine enhances implicit memory in Alzheimer patients.

Neurology 1996;46:420424.

[83] Schwob JE, Fuller T, Price JL, Olney JW. Widespread patterns of

neuronal damage following systemic or intracerebral injections of

kainic acid: a histological study. Neuroscience 1980;5:9911014.

[84] Seligman ME, Maier SF. Failure to escape traumatic shock. J Exp

Psychol 1967;74:19.

[85] Shimano H, Ishibashi S, Murase T, Gotohda T, Yamada N, Takaku

F, Ohtomo E. Plasma apolipoproteins in patients with multi-infarct

dementia. Atherosclerosis 1989;79:257260.

[86] Speck CE, Kukull WA, Brenner DE, Bowen JD, McCormick WC,

Teri L, Pfanschmidt ML, Thompson JD, Larson EB. History of

depression as a risk factor for Alzheimers disease. Epidemiology

1995;5:366396.

[87] Stein-Behrens BA, Elliott EM, Miller CA, Schilling JW, Newcombe

R, Sapolsky RM. Glucocorticoids exacerbate kainic acid-induced

extracellular accumulation of excitatory amino acids in the rat

hippocampus. J Neurochem 1992;58:17301735.

[88] Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R.

Influence of education and occupation on the incidence of Alzhei-

mers disease. JAMA 1994;271:10041010.[89] St George-Hyslop PH, et al. Genetic linkage studies suggest that

Alzheimers disease is not a single homogeneous disorder. Nature

1990;347:194197.

[90] Stokes PE. The potential role of excessive cortisol induced by HPA

hyperfunction in the pathogenesis of depression. Eur Neuropsycho-

pharmacol 1995;5(Suppl):7782.

[91] Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M,

Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity

binding to b-amyloid and increased frequency of type 4 allele in

late-onset familial Alzheimers disease. Proc Natl Acad Sci USA

1993;90:19771981.

[92] Tamaru M, Yoneda Y, Ogita K, Shimizu J, Nagata Y. Age-related

decreases of the N-methyl-d-aspartate receptor complex in the rat

cerebral cortex and hippocampus. Brain Res 1991;542:8390.

[93] Uno H, Tamara R, Else JG, Suleman MA, Sapolsky RM. Hippocam-pal damage associated with prolonged and fatal stress in primates. J

Neurosci 1989;9:17051711.

[94] van Duijn CM, Clayton D, Chandra V, Fratiglioni L, Graves AB,

Heyman A, Jorm AF, Kokmen E, Kondo K, Mortimer JA, et al.

Familial aggregation of Alzheimers disease and related disorders:

a colloborative re-analysis of case-control studies. Int J Epidemiol

1991;20(Suppl 2):S1320.

[95] Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical

dendrites of hippocampal CA3 pyramidal neurons. Brain Res

1992;588:341345.

[96] Weinstock M. The pharmacotherapy of Alzheimers disease based

on the cholinergic hypothesis. An update. Neurodegeneration

1995;4:349356.

[97] Wolley CS, Gould E, McEwen BS. Exposure to excess glucocorti-

coids alters dendrite morphology of adult hippocampal pyramidalneurons. Brain Res 1990;531:225231.

[98] Yehuda R, Keefe RS, Harvey PD, Levengood RA, Gerber DK, Geni

J, Siever LJ. Learning and memory in combat veterans with post-

traumatic stress disorder. Am J Psychiat 1995;152:137139.

[99] Zhang M, Katzman R, Salmon D, JinH, Cai G, Wang Z, Qu G, Grant

I, Yu E, Levy D, Klauber M, Liu WT. The prevalence of dementia

and Alzheimers disease in Shangai, China: impact of age, gender,

and education. Ann Neurol 1990;27:428437.

[100] Zyzak DR, Otto T, Eichenbaum H, Gallagher M. Cognitive decline

associated with normal aging in rats: a neuropsychological approach.

Learn Mem 1995;2:116.


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