Acetylcholine and brain aging

Pharmacological Research CommunicationS, Vol. 20, No. 2, 1988

91

ACETYLCHOLINE AND BRAIN AGING Giancarlo Pepeu Department of Preclinical and C1inical Pharmacology, University of Florence, Viale Morgagni 65, 50134 Florence, Italy

Received in final form 7 January 1988

Brain" aging commonly includes two pathological

conditions,

senile

dementia of Alzheimer and Alzheimer's type (SDAT) and multinfarct

dementia

(MID), and the "age-associated memory impairment" (Crook et al,

1986) for

which the borderline between normality and pathology has not been yet defined. generally

Parkinson's disease could also be included,

fully

but this condition is

kept separated perhaps because its pathogenesis is better

knQwn

and its therapy firmly established. The finding by Davies and Maloney (1976), rapidly confirmed by many other investigators (see ref. in Bartus et al., 1982), that in the cerebral cortex and hippocampus of subjects affected by SDATthere is a marked reduction

in

choline acetyltransferase (CHAT) activity suggested a lack of acetylcholine (ACh) as a cause of the brain dysfunction in senile dementia.The decrease in ChAT activity depends upon the degeneration of the cholinergic the forebrain

neurons in

nuclei including the nucleus basalis and the nuclei

of

the

diagonal band and septum medialis (Price et at., 1982) and is related to the number of

senile

plaques in the cerebral cortex

(Perry et

at.

1978).

Contrasting reports exist on the changes in muscarinic receptors associated

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© 1988 The Italian Pharmacological Society

92

Pharmaco~gicalReseazch Communications, Vol.2GNo. ~ 1988

with the degeneration of the forebrain cholinergic neurons.

i n i t i a l l y found by most investigators ~Bartus et al., decreases restricted

to

No changes were

1982). More recently~

discrete brain regions (Rinne et

al.,

1985) or

specific receptor subtypes ( Nordberg et al., 1986) have been described. In

recent years i t has been shown that in the brain of

there is the loss of many other neurotransmitters,

SDAT patients

including noradrenaline,

dopamine, serotonin, GABA, somatostatin and substance P. (see ref. in Hardy et

ai.,1985).

This

makesthe parallelism between the decrease in ACh in

SDAT and the decrease in dopamine in Parkinson's disease untenable. However, there are many indications critical

that the cholinergic

hypofunction plays a

role in the cognitive and memory alterations of SDAT. I) In

SDAT

patients a relationship has been consistently demonstrated between cognitive impai~nent and neurotrasmitter decrease only when mental scores are plotted against cortical

ChaT activity measured in biopsy (Sims et

Francis

1985) and autopsy samples (Perry et al.,

et

destruction

al., of

the nucleus basalis in the rat is

deficits (Pepeu et al, cognitive therapeutic

1980;

1978). 2)

followed by

The

cognitive

1986). 3) SDATpatients show a marked behavioral and

sensitivity to scopolamine ( Sunderland et ai.,1985). results

al.,

5) Limited

in SDATpatients have been only obtained with

drugs

acting on brain cholinergic mechanisms (Crook, 1985). A decrease in

ChATactivity has been also found in cortical

areas in

those cases of Parkinson's disease where a cognitive deficit occurred while ChAT activity cognitive aI.,

was normal in the cases of

impairment (Candy et al.,

1978) and alcoholic

Parkinson's disease with

no

1983). Mixed type dementia (Perry

et

dementia (Antuono e t a ] . ,

1980) are also

Pharmaco/ogica/Reseazch Commun~ations, VoL2~ No. 2,1988

93

characterized by a decrease i n c o r t i c a l ChAT a c t i v i t y . Conversely, no change

in

ChAT activity

was found in MID (Perry et

at.,

1978) and slightly ~

decreased ChAT activity with norma] ACh formation was found in samples~taken from non-SOATdemented patients (Sims e t al,

1983). Therefore, dementia

is not always associated with a cholinergic deficit. The word dementia applies to different

patterns of

neuropsychological

impairment (Gainotti et al.,19BO) and according to Perez et ai.(1975)

SDAT

patients consistently show a more severe deterioration than MID patients. An analysis

of the differences in mental deterioration between dementias with

and without cholinergic impairment could help in defining of which cognitive functions are responsible the cortical and hippocampal cholinergic pathways. On the other hand, the normal ChAT levels found in MID demonstrate that

in

this form of dementia there is no loss of cholinergic n~urons. They are not an indication of the function of the neurons i~nsitu, focally

inadequate oxygen supply. Inbrain slices

release and synthesis (see ref. that

in

MID the

under conditions

of

hypoxia reduces ACh

in Tucek, 1984). Therefore,the possibility

function of the cho]inergic

neurons might be locally

impaired can not be excluded. The decline in the a b i l i t y to remember certain types of information which occurs in many healthy individuals during the later decades of l i f e has been recently defined age-associated memory impairment (Crook et al., 1986). This condition also occurs in

aging animals (Ingram, 1985) and remarkable

analogies have been observed between memorydeficits in old monkeys and men (Dean and Bartus,

1985). The hypothesis that the cognitive

disturbances occurring with aging may reflect some disorder of

and memory cholinergic

Pharmacolog~a/Research Commun~ations, Vo~ 2~ No.Z 1988

94

neurotransmitter

function

was put

forward by Drachman et

comparing the memory and cognitive deficits,

ai.(1974)

by

induced in young subjects

by

central cholinergic blockade, with the performance of aged subjects. Even i f no consistent decrease in ChAT activity has been found in aged animals and humans but only, al.,

sometimes, a decrease in muscarinic receptors (Bartus et

1982) many experimental results,

listed

below, support Drachman's

hypothesis. I) In v i t r o (Pedata et a1.,1983; Vannucchi and Pepeu, 1987) and in vivo (Consolo et al.,

1987) studies demonstrate a marked decrease in ACh

release from the cerebral cortex and hippocampus in aging rats. 2) According to

Gibson and Peterson (1981) there is a reduced ACh synthesis

in

aging

rodents. 3) The selective age-related shrinkage of the cortically projecting cholinergic neurons observed by Mesulam et al (1987) in old mice may account for

the decline in the function of cholinergic neurons.

4) Fisher

(1987) obtained both an amelioration of the atrophy of neurons

the

et

al.

cholinergic

in aged rats and an improvement of their spatial memory impairment

by intraventricular infusion of nerve growth factor (NGF). 5) A consistent improvement

in memory and cognitives function has been observed in

normal

aged volunteer subjects treated with physostigmine (Drachman and Sahakian, 1980) and in aging monkeys treated with direct and indirect

cholinomimetic

agents (Bartus et al., 1983). Differences in the severity of the cholinergic hypofunction could explain the

large

individual

variability in the severity

of

the

age-associated

memory impairment and the d i f f i c u l t y in distiguishing its more severe forms from i n i t i a l chollnergic

SDAT. In

the latter case, however, there

is

a loss

neurons while in "normal" aging there is a hypofunction of

of the

Pharmaco~gicalResearchCommunication~ t ~ 20 No.~ 1988

cholinergic

95

neurons which appears to be reversible as shown in the rat

by

the morphological recovery obtained by Fisher et al (1987) with NGF infusion and

the

recovery

in

ACh release obtained

by

phosphatidylserine

administration (Pedata et al., 1985, Vannucchi and Pepeu, I~87) A shadow is cast, al.,

however, on the "cholinergic hypothesis" (Bartus et

1982) in cognitive deterioration by the limited

obtained

in

therapeutic

all forms of aging brain by the administration of

success

direct

and

indirect cholinomimetic agents (Crooks, 1985). Several explanations can be offered

for

regulation

this, following

Fakahany, 1981) to treatment, that

ranging from a rapid receptor desensitization and down cholinomimetic administration

(Richelson and

EI-

the limitations in the doses used and duration of

the

imposedby the toxicity of the drugs available.

The possibility

restoring the normal function of the cholinergic neurons may require

the presence of co-transmitters or the integrity of other

neurotransmitter

systems impaired by SDAT and aging should also be envisaged. Not enough is yet

known on the physiological and pathological changes occurring

brain aging process, in spite of the large body of information in the last 10 years,

in

the

accumu)ated

and the development of effective drugs for the aging

brain is s t i l l a challenge for the neuroscientists.

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Pharmacological Research Communications, VoL 20, No. 2, 1988

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