The neurochemistry of Alzheimer's disease and senile dementia

The Neurochemistry of Alzheimer’s Disease and SeniIe Dementia

Peter Davies* Departments of Neuropatkology a n d Neuroscience,

Albert Einstein College of Medicine, 1 3 0 0 M o r r i s P a r k Avenue, Bronx, New York I 0 4 6 1

I. Introduction ............................................................ 221 11. The Prime Example: Parkinson‘s Disease .................................. 222

111. What is Alzheimer’s Disease? ............................................ 223 IV. Neurochemical Studies of the Alzheimer Brain ............................ 223

A. Acetylcholine ....................................................... 223 B. Dopamine, Noradrenalin, and Serotonin ............................... 225 C. Amino Acids ........................................................ 228 D. Neuropeptides ...................................................... 228 E. Summary of Neurochemical Data ..................................... 229

V. The Nature of the Cholinergic Defect .................................... 230 VI. Are the Symptoms of Alzheimer’s Disease Due to a Deficiency

of Acetylcholine? ....................................................... 231 V!1. Can a Deficiency of Brain Acetylcholine be Treated? ....................... 232

VIII. Why are Cholingeric Neurons Specifically Affected by Alzheimer‘s Disease? ............................................................... 233

Ix. Summary .............................................................. 234 References .................................................................. 234

I. INTRODUCTION

The brain is an organ uniquely specialized for cell to cell communica- tion, the function of which is highly dependent on the ability of nerve cells to receive and transmit information. Alarge part of this information transfer is mediated by the release of chemicals from specialized regions of nerve cells, and the interaction of these chemicals with receptor structures on the target cell. About 25 substances have been identified in the mammalian brain that appear to function as chemical message carriers, and these are collectively known as neurotransmitters. Nerve cells of the brain can thus be divided into about 25 different groups based on the nature of the neurotransmitter they use to communicate with other cells. While it is possible also to categorize cells on other grounds,

*Recipient of the Sixth CIBA Geigy Drew Award in Biomedical Research, October 13, 1982, Drew University, Madison, NJ.

Medicinal Research Reviews, Vol. 3, No. 3, 221-236(1983) @ 1983 by John Wiley & Sons, Inc. CCC 0198-6325/83/030221-16$02.60

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such as size, shape, or location, these definitions are of minor importance to this review. The major question to be addressed here is whether neurologic diseases, and in particular Alzheimer’s disease, affects all classes of neurons equally, or affects only those neurons which use one particular chemical as their neurotransmitter. As we will see, there is already an example of a neurologic disease which shows a remarkable degree of specificity, and the resulting chemical deficiency is in large part treatable by replacement therapy. Obviously, our hope is that while all neurologic disorders are unlikely to prove so ameanable, a better understanding of the neurochemistry of these conditions will result in significant advances in treatment. Further, the demonstration that certain diseases selectively attack specific types of nerve cell ought to provide clues to the causes and prevention of these conditions.

11. THE PRIME EXAMPLE: PARKINSON’S DISEASE Neurochemical work on Parkinson’s disease in the later 1950s and

early 1960s revealed that certain brain regions were markedly deficient in dopamine (dihydroxyphenylethylamine).’ This chemical is almost certainly a neurotransmitter used by cells that have their cell bodies in the substantia nigra, and send projections up to the caudate nucleus and putamen. The degeneration of these cells had already been described by neuropathologists, but it was the marked losses of dopamine that really confirmed the nature of the transmitter they used. It was also known that the caudate nucleus and putamen were involved in the control of movement, and it was postulated that the loss of dopamine from these brain regions caused the movement disorders that characterize Parkin- son’s disease. The logical choice of L-Dopa (dihydroxyphenylalanine) for the treatment of this disease was based on a knowledge of the biosynthesis of dopamine in brain tissue: tyrosine is hydroxylated by tyrosine hydroxylase and the resulting L-dopa is decarboxylated by aromatic amino acid decarboxylase to form dopamine. History shows that this was indeed a wise choice: despite some problems, there can be little doubt of the value of this agent in the treatment of Parkinson’s d’ Isease.

There are two points to be taken from this example: (1) That a disease

Peter Davies i s Associate Professor i n the Department of Neuroscience at Alber t Einstein College of Medicine in N e w York, N e w York. H e previously had a n appointment at Medical Research Council’s Brain Metabol i sm U n i t , Edinburgh, Scotland from 1975-1977. He was born i n Tredegar, W a l e s and received the B.Sc. w i th Honors, 1st Class i n Biochemistry i n 1 9 7 1 and the Ph .D . i n 1 9 7 4 a f the UniversityofLeeds,England. Healsodid postgraduatetrainingfrom 7 9 7 1 - 1 9 7 4 i n the LaboratoryofProfessor D. S . Robinson at the UniversityofLeeds,England and was George Gu thr i e Research Fellow for 1 9 7 4 - 1 9 7 5 i n the Department of Pharmacology at the University of Edinburgh, Scotland. He received the C I B A - G e i g y Drew A w a r d in Biomedical Research for 1 9 8 2 .

ALZHEIMER’S DISEASE 223

exists in which there is selective destruction of a group of nerve cells defined by the nature of their neurotransmitter; and (2 ) That the resulting chemical deficiency can be treated so as to alleviate many of the symptoms of the disease. However we do not yet know why or how these cells are specifically destroyed, nor can we halt the progress of the disease. The fact remains that we can provide a considerable improve ment in the lives of Parkinson patients. There are already some indications that such benefits may also be possible for patients with Alzheimer’s disease.

111. WHAT IS ALZHEIMER‘S DISEASE? The diagnosis of Alzheimer’s disease can only be made definitively by

direct, microscopic examination of brain tissue. In 1906, Alois Alzheimer observed two microscopic abnormalities in the brain of a 53 year old woman who died after suffering from profound memory loss, disorientation and a marked deterioration of intellectual abilities. The presence of these two lesions, the neuritic plaque and the neurofibrillary tangle, remain the pathologic entities which define Alzheimer’s disease. There are several good reviews of the structures of the plaque and tangle.2 Perhaps because Alzheimer’s first patient was a relatively young woman, the disease was until quite recently considered to be a presenile dementia: that is, a dementia occurring in persons under 65 years of age. It is only in the last few years that studies of the occurrence of plaques and tangles in the brains of elderly victims of ”senile dementia”or “organic brain syndrome” have revealed that at least 50% of such patients have Alzheimer-type pathology as the only abnormality in the brain. Since there are over 3 million individuals aged over 65 who are demented to some degree in the USA alone, we assume that there are at least 1.5 million victims of Alzheimer’s d i ~ e a s e . ~ , ~

The problem in the diagnosis of Alzheimer’s disease is that there is no positive test: the clinician has to rule out other causes of dementia such as strokes, microvascular disease, brain tumors, thyroid dysfunction, drug reactions, severe depression, and a host of other conditions that can cause intellectual deficits in elderly p e ~ p l e . ~ Only when all these problems have been eliminated as a cause of the symptoms should a diagnosis of Alzheimer’s disease be accepted. Needless to say, it is easier to label an elderly patient as ”senile” than to go through all the necessary procedures to make the tentative diagnosis of Alzheimer’s disease.

IV. NEUROCHEMICAL STUDIES OF THE ALZHEIMER BRAIN A. Acetylcholine

In 1975, in collaboration with McKay, Maloney, and Ashcroft, I began what was designed to be a systematic investigation of neurotransmitters in Alzheimer’s disease. We had chosen five groups of nerve cells to investigate, comparing autopsy brain tissue from normal individuals

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with that from cases of Alzheimer's d i ~ e a s e . ~ , ~ The five groups were those that used noradrenalin, dopamine, serotonin, acetyl choline, and gamma-aminobutyric acid as neurotransmitters. Because we planned to work on tissue removed from patients several hours after death, we attempted to select "markers" for each system which were not degraded by autolysis after death. The term "marker" is used here to denote a chemical or enzyme that can be measured to provide an index of the state of particular class of cells. For example, the concentration of noradrenalin in a particular brain region can be used to determine the state of health of noradrenalin-releasing neurons. A listing of some of the other markers in current use is to be found in Table I, along with their relationship to the neurotransmitter system and an assessment of their stability in the human brain after death.

We immediately realized that the activities of two enzymes, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) were much reduced in the brains of patients with Alzheimer's disease. ChAT is the enzyme responsible for the synthesis of acetylcholine, and it is found only within neurons which use this chemical as their neurotransmitter. While AChE is also heavily concentrated in neurons using acetylcholine, some other cells have this enzyme, and it is therefore not quite such a good marker of the so-called cholinergic neurons. So clear and consistant were those reductions in these two enzyme activities that we wrote the first paper when studies were completed on just three cases.' We later learned that two other groups in England had made almost identical observations on ChAT activities in the Alzheimer brain, and the three groups published almost simultaneously.8-" Since those early reports, confirmation and extension of these findings has come from several different laboratories around the world,'2-18 and it can no longer be doubted that almost every brain in which large numbers of plaques and tangles are found will show reductions in ChAT activity from 50% to 90% below those in the normal brain. Representative results from my own group are displayed in Figure 1. As additional data is added, it seems certain that Alzheimer's disease has a major deleterious impact on neurons that use acetylcholine for neurotransmission. This was most recently confirmed by Bowen's g r o ~ p , ' ~ , ~ ~ who showed that biopsy tissue taken from Alzheimer patients showed considerable reduction in the ability to produce acetylcholine from glucose, while being able to oxidize. glucose to carbon dioxide at normal or better than normal rates. This provided a most important confirmation of the results obtained with autopsied brain tissue, because it was the first demonstration that living Alzheimer patients had difficulties with acetylcholine transmission. The beautiful experiments of Bowen's group also demonstrated another important point, which we will return to later. It is now well accepted that the cholinergic neurons are affected by Alzheimer's disease, but we must now consider whether or not they are selectively vulnerable to this d' isease.


Table I Markers for the Study of Neurotransmitter Systems’

Relation to Postmortem Marker Transmitter Stability Specific?

1.

2.

3.

4.

5.

Acetyl Choline Acetylcholine Choline acetyltransferase Acetylcholinesterase High affinity choline uptake G A B A GABA Glutamic acid decarboxylase Dopamine Dopamine Homovanillic acid Dihydroxyphen ylacetic acid Tyrosine hydroxylase Aromatic amino acid decarboxylase Noradrenalin Noradrenalin 3-Hydroxy-4-methoxyphenylglycol Tyrosine hydroxylase Aromatic amino acid decarboxylase Dopamine-beta-hydroxylase Serotonin Serotonin 5-Hydroxyindoleacetic acid Tryptophan h ydroxylase Aromatic acid decarboxylase

Transmitter Biosynthetic enzyme Degradative enzyme Supplies substrate

Transmitter Biosynthetic enzyme

Transmitter Metabolite Metabolite Biosynthetic enzyme Biosynthetic enzyme

Transmitter Metabolite Biosynthetic enzyme Biosynthetic enzyme Biosynthetic enzyme

Transmitter Metabolite Biosynthetic enzyme Biosynthetic enzyme

unstable stable stable stable(?)

stableb stable‘

unstable stable stable unstable stable

unstable stable unstable stable questionable

unstable stable unstable stable

aNote that a specific marker is a compound found only in or around a single cell type. A no in the specific? column means that other cell types also contain the compound: In some cases, degeneration of a specific cell type does rerlult in the loss of nonspecific as well as specific markers, so they are not useless.

bGABA concentrations actually increase after death in animals, but stabilize very quickly, and remain stable for at least 36 h.

‘Although glutamic acid decarboxylase is stable once death has occurred, there appear t o be marked effects of the mode of death on this enzyme activity. A slow lingering death can produce substantial losses of activity by a mechanism perhaps involving anoxia.

dTyrosine hydroxylase is found in both dopaminergic and noradreneric neurons; it is useful as a marker in some brain regions which contain either one of the transmitter systems in much greater density than the other. The same is true of dopamine: it is a precursor of noradrenalin in noradrenergic cells, and is found in low concentration in these neurons.

8. Dopamine, Noradrenalin, and Serotonin

There have been several reports over the last 10 years which suggested that neurons using dopamine, noradrenalin, or serotonin were affected by Alzheimer’s disease. However, more recent studies raise several questions. One way to examine the status of the dopaminergic cells is to measure the concentrations of metabolites of dopamine in the cerebro-

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L O c c i p i t a l 1 Anterior c i n a u l a t e 1 Superior temporal 1 Mid temporal I I n f e r i o r temporal l

Hippocampus 1

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ALZHEIMER ChAT AS PERCENT OF CONTROL

PERCENT

0 5 10 15 20 25 30 1 1 I I I 1

Mid f r o n t a l I I n f e r i o r p a r i e t a l 1

spinal fluid. Such investigations reveal the expected decreased concentration of one such metabolite, homovanillic acid (HVA) in samples from Parkinson patients.’ It was reported that HVA levels were also reduced in patients with Alzheimer’s but other workers have been unable to confirm this finding.23,24 In the most impressive study, Bowen et examined cerebrospinal fluid from patients who had brain biopsies to establish the cause of dementia. Since the pathologic diagnosis is definitive, this study is much better controlled than those that used purely clinical criteria for selecting patients for investigation. Bowen found that those patients with plaques and tangles in biopsy tissue did not have low cerebrospinal fluid HVA levels, but that a few demented individuals free of plaques and tangles (and therefore free of Alzheimer‘s disease) showed very low HVA concentrations. This study con- firms what neuropathologists already knew: the clinical diagnosis of Alzheimer’s disease is not 100% accurate, and there are other conditions, some as yet poorly defined, that can cause dementia. In those cerebre spinal fluid studies which relied on purely clinical criteria for the selection of patients, the inclusion of various numbers of non-Alzheimer cases could easily bias the results. A further complication is that Parkinson’s disease is not uncommon among elderly demented individuals, and the inclusion in investigations of Alzheimer’s disease of patients with a disease with profound effects on dopamine cells will again produce conflicting results.

In examinations of autopsied brain tissue, greater control over the material should be possible, because a detailed microscopic examination


of the substantia nigra will determine whether or not Parkinson’s disease was present, even if it was not obvious on clinical testing. It would seem reasonable to divide Alzheimer cases into two groups: (a) those free of any Parkinson’s disease, and (b) those with substantia nigra pathology. Unfortunately, this has only rarely been done, and this writer is not aware of any papers in which the incidence of substantia nigra pathology in Alzheimer patients has been reported, let alone the neurochemistry of these patients. The one published study of measurements of dopamine and its metabolites in which cases with nigral pathology were excluded failed to show any evidence for damage to the dopaminergic system.26

There is perhaps one other line of evidence indicating that no significant losses of dopamine occur in Alzheimer’s disease, and that is the failure of r-dopa to produce any beneficial effects when administered to such individual^.^^^^^ It is known from a variety of animal and human work that L-dopa does increase brain dopamine concentrations, and enhances dopaminergic transmission.’ Its failure to produce any improvement in Alzheimer patients suggests that none of the significant symptoms of this disease result from losses of dopamine.

With regard to noradrenalin, many of the above considerations must apply. Small groups of neurons in the brain stem send projections to large regions of brain to deliver noradrenalin. The major noradrenergic cell group is in the locus coereleus, and degeneration of cells in this region of brain from cases of Alzheimer’s disease has been r e p ~ r t e d , ~ ~ ’ ~ ~ and this is presumed to correlate with losses of noradrenalin from other brain regions. However, it would seem that the degeneration of the locus coereleus is not a consistent finding in Alzheimer’s disease, and the losses of noradrenalin that have been reported (SO-SO%) are not as marked as those of ChAT (60-90%).29,30 It is tempting to speculate that degeneration of the noradrenalin neurons is a coincidental event in some cases of Alzheimer’s disease. When degeneration of the dopamine cells of the substantia nigra is seen, we call the condition Parkinson’s disease: when the brain also has plaques and tangles, we say the patient had two coincident diseases. There is no reason to assume that degeneration of the noradrenalin cells is the result of Alzheimer’s disease, and not the result of some coincident disease process. There is simply insufficient evidence at this time to choose between these alternatives. One further tempting speculation is that degeneration of the noradrenalin system might be expected to result in depression: although the evidence is far from complete, drugs like reserpine that deplete the brain of catechol- amines (including noradrenalin) can result in depression. There is no doubt that a significant number of demented patients are also depressed, and in some cases the depression will respond to appropriate drug treatment. However, in very few cases does this therapy produce significant improvement in the dementia.

Much of what has been written in this section applies to consideration of those neurons which use serotonin (5-hydroxytryptamine) as trans-

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mitter, although there have been few studies of these cells. It will be important to ask whether degeneration of serotonergic cells is a consisfent feature of the Alzheimer brain, and to attempt to relate losses (if any) of this transmitter to specific symptoms of this disease. The limited amount of information available on this point does not suggest the presence of any major abnormalities in this transmitter system.31

C. Amino Acids

There are a number of amino acids that appear to be used as neurotransmitters in the mammalian brain. These include gamma-amino butyric acid (GABA), glutamic acid, aspartic acid, glycine, and taurine. There is a measure of agreement on the status of GABA neurons in the Alzheimer brain: they appear in most studies to be well preserved, as judged by measurements of the activity of glutamic acid decarbox- y l a s e , l Z , 13,32 and by measurements of GABA concentration^.^^ While there may be some minor losses in some brain regions from very severe cases, these are neither consistent nor dramatic enough to play any significant role in the symptoms of this disease. The other four amino acids are very difficult to study, because the only marker we have is the concentration of the amino acid itself. Since these compounds are involved in a large number of metabolic reactions, only a small percentage of the totalamount present in the brainis involved in neurotransmission. Thus it is impossible a t this time to determine whether or not changes in amino acids concentrations would accompany a loss of the specific neurons using the compound as a transmitter. In this situation, it is difficult to know how to interpret the data published by Tarbit e t al.,33 which showed normal levels of these amino acids in the Alzheimer brain. Until additional markers can be found, the status of amino acid-releasing neurons will remain uncertain.

D. Neuropeptides

There are several peptides in the mammalian brain which appear to have some role in n e u r o t r a n s m i ~ s i o n . ~ ~ , ~ ~ They are more often called neuromodulators than neurotransmitters, because their actions are, in general, more long-lasting than those of the simpler substances covered in the previous sections. Whether or not this nomenclature has any real meaning is not yet clear, but these peptides clearly have the ability of excite or inhibit neuronal activity a t very low concentrations, and are present in neurons and released by calcium-dependent, potassium- stimulated processes, very like those governing the release of the better- known neurotransmitter^.^^ Concentrations of several of these peptides have been measured in autopsied brain tissue from Alzheimer case^,^^-^' and the results obtained by several groups are summarized in Table 11. As the table shows, only two peptides have been reported to be present in subnormal concentrations in the Alzheimer brain, somatostatin and


Table I1 Neuropeptides in the Alzheimer Brain

Present in normal concentration Reference NO.

Vasoactive Intestinal Peptide 41, 45 Cholecystokinin Octapeptide 43,45 Vasopressin 42

Substance P 44,45 Maybe reduced

Present in reduced concentration Somatostatin 37, 38, 40, 45

substance P. Of these two, only somatostatin has been found to be reduced by more than one laboratory.

Before discussing the potential significance of reductions in n e u r e peptides for Alzheimer’s disease, a few cautionary words are needed. As with the amino acid transmitters, the only marker for peptide neurons available is the concentration of the peptide in question. Of all the markers for neurotransmitter systems available, the concentration of the transmitter itself is, in general, the least reliable. For example, under a variety of conditions that increase or decrease transmission by acetylcholine, the concentration of acetylcholine can go up, down, or remain the same in a quite unpredictable fashion. Whether or not this is true of neuropeptides is not yet known, so we must be very cautious in equating changes in peptide concentration with a loss of peptidergic neurons. This is especially true in the case of somatostatin: stress induced in rats by forced swimming causes a marked reduction in the concentration of somatostatin in the hypothalamus not through a loss of cells, but because there is a massive release of the peptide.

With the above considerations in mind, it must be held equally possible that there is a loss of somatostatin neurons in the Alzheimer brain, or that there is excessive release of somatostatin causing a depletion of tissue stores. We do not yet have the information that would allow us to choose between these alternatives.

E. Summary of Neurochemical Data

It would seem at this time that we have very good evidence to show that neurons which use acetylcholine for transmission are markedly affected by Alzheimer’s disease. There are also strong indications for the specific involvement of these cells: with the possible exception of somate statin-containing neurons, other neurotransmitter systems appear to be either well-preserved, or to be involved only in the minority of cases. There are four questions that now need to be addressed: (A) What is the problem with the cholinergic neurons? (B) Is it reasonable to attribute the major symptoms of Alzheimer’s disease to deficiency of acetyl-

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choline? (C) How can we best treat an acetylcholine deficiency? (D) Why are cholinergic neurons specifically affected by Alzheimer’s disease?

V. THE NATURE OF THE CHOLINERGIC DEFECT

Ever since the discovery of the losses of ChAT and AChE in the brains of patients with Alzheimer’s disease, there has been speculation as to the nature of the problem with the cholinergic neuron. There are three possible explanations for the losses of enzyme activities. The first and simplest explanation, put forward in 1976,’ is that cholinergic neurons are reduced in number in proportion to the losses of ChAT activity (60-9OYo). The second possibility is that the terminals of cholinergic neurons, at which ChAT and AChE are highly concentrated, are lost but that the cell bodies remain. The third possibility is that the entire cholinergic cells survives, but shuts down the production of the two enzymes. While we are still not in a position to choose between these three possibilities, it is the first explanation which has received the most support.

The major problem in this area has been our lack of knowledge concerning the location of cholinergic cell bodies in the mammalian brain. Avariety of animal studies suggests that there are few, if any, cholinergic cell bodies in the cerebral cortex or hippocampus; thus most of the ChAT and AChE activities in these regions are contained within nerve terminal^.^^-^' More recent work seems to indicate that the cells bodies sending the cholinergic terminals to the cortex and hippocampus lie deep within the brain, forming a sheet of cells that extend from the septum down and along the basal surface, to include the nucleus basalis of the substantia innominata. The location of the cholinergic cell bodies is shown diagrammatically in Figure 2 . If there is a loss of cholinergic neurons in Alzheimer’s disease, then a loss of cell bodies from the septum and nucleus basalis would be predicted. Evidence of severe cell loss from the nucleus basalis region has recently been reported by Whitehouse et a1.51,5Z In my opinion, this evidence is not yet definitive, because of problems in being certain that cholinergic neurons are being counted. At this time there is no definitive means of identifying cholinergic neurons in the human brain. The ideal in this regard would be a histochemical or immunohistochemical technique for visualizing cells containing the most specific marker of cholinergic neurons, Ch AT. The recent development of specific antibodies to this enzyme has made immunohistochemical studies of animal brain p0ssible,5~ but there have yet to be reports of success with this technique on human autopsy brain tissue. A related problem is that without this specific tool, it is impossible to know the extent and precise location of the cholinergic cells, and hence it is difficult to select regions in which to count cells. While it seems likely that Alzheimer’s disease results in severe reductions in the number of


Figure 2. The location of the cell bodies that send acetylcholine-releasing terminals to the cerebral cortex is shown diagrammatically. There are at least three groups of cells, indicated as the heavy black bands. On the single brain section drawn here, it is not possible to appreciate the quite extensive anterior to posterior distribution of these cell groups. Abbreviations used are: P = putamen, GP = globus pallidus, C = caudate nucleus, CC = corpus callosum, AC = anterior commisure, FC = frontal cortex, STG = superior temporal gyrus, and MTG = midtemporal gyrus.

cholinergic neurons in the brain, further work is still needed to clarify this point.

VI. ARE THE SYMPTOMS OF ALZHEIMER’S DISEASE DUE TO A DEFICIENCY OF ACETYLCHOLINE?

O n this point there has been a surprising degree of general agreement. The reason for this agreement is that a wealth of work over the last 20 years has demonstrated the importance of neurotransmission by acetylcholine in memory f ~ n c t i o n . ~ * * ~ ~ In laboratory rats and mice, drugs or brain lesions which interfere with cholinergic transmission can be shown to disrupt performance on a variety of tasks involving memory. In humans too, anticholinergic drugs like scopolamine and atropine can impair memory function, sometimes producing confusional states that in the short term look very similar to dementia.55 Drugs which block the actions of noradrenalin, dopamine, or serotonin simply do not produce the same pattern of symptoms, further suggesting that deficits in these systems are not involved in the symptoms of most Alzheimer patients. In general terms, the major symptoms of Alzheimer’s disease, memory loss, disorientation, and declining ability to perform complex mental tasks can be reasonably held to be due to a shortage of acetylcholine.

It is not at all clear whether or not there are specific behavioral deficits associated with the reported decreases in somatostatin in the Alzheimer

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brain. We know next to nothing about the possible role of this peptide in human behavior.

VII. CAN A DEFICIENCY OF BRAIN ACETYLCHOLINE BE TREATED?

The answer to this question surely must be yes, but at the moment there is no really good evidence that this has been achieved. The earliest attempts to treat the acetylcholine deficiency in Alzheimer’s disease involved the administration of large doses of choline or phosphatidyl- choline ( l e ~ i t h i n ) . ~ ~ ’ ~ ~ These trials were modeled after the success of the so-called precursor therapy of Parkinson‘s disease with L-dopa, which was described earlier. Unfortunately, none of these trials has been able to show any significant improvement of the symptoms of Alzheimer patients. The reason for the apparent failure of precursor therapy for Alzheimer’s disease is not yet entirely clear, but there are several points that are worth making. The most obvious way to begin is to ask what factors control the rate of acetylcholine synthesis in the brain, and the answer is that we do not really know. It has been suggested that the availability of choline is one factor,5R but some workers have been unable to demonstrate any effects of increasing choline concentrations on the rate of synthesis of ace ty l~ho l ine .~~ Further, Bowen’s work with biopsy tissue demonstrated reduced acetylcholine synthesis even in the presence of choline concentrations at least 100 times greater than those found in the The availability of the second substrate for ChAT, acetyl coenzyme A has also been suggested as a rate-limiting factor.60,61 There is some evidence that would support this notion from experiments which have shown that acetylcholine synthesis is very sensitive to drugs which interfere with the oxidation of glucose or pyruvate to produce acetyl coenzyme A. If precursor therapy is to be pursued, it might be important to ensure that supplies of both precursors are increased: How acetyl coenzyme A availability can be elevated is a subject for future research. This is a controversial area currently, with several mechanisms being proposed to explain how acetyl coenzyme A made in mitochondria is made available for acetylcholine synthesis in the cytoplasm.60

Another approach to treat an acetylcholine deficiency is to attempt to slow down the degradation of the transmitter by inhibition of AChE. Trials of physostigmine, a cholinesterase inhibitor that has been used in medicine for more than 150 years, have recently been started. Prelimi- nary results are positive, but not very dramatic. One of the major problems with the use of cholinesterase inhibitors is the toxicity of this class of compounds. Acetylcholine is used as a neurotransmitter at many sites outside the brain, including most of the neuromuscular junctions. The effects of overdoses of cholinesterase inhibitors are well-known: most dramatically to the military, as many of the nerve gases and chemical warfare weapons are cholinesterase inhibitors.6* Whether or


not drugs of this class will be developed which are specific for brain AChE and harmless to the peripheral enzymes is not known, but the search for such agents would seem worthwhile.

Still another approach to treatment might be to use compounds that mimic the action of acetylcholine in the brain (cholinomimetics or cholinergic agonists). The two types of acetylcholine receptor, muscarinic and nicotinic, appear to be quite well-preserved in the brains of Alzheimer patients, and may represent sites to aim at.63’64 The current opinion seems to be that muscarinic acetylcholine agonists would be most appropriate, because there are many more muscarinic than nicotinic receptors in the brain.65 Again, a major problem with the use of cholinergic agonists is likely to be toxicity: Although most neuromus cular junctions use nicotinic receptors, muscarinic receptors are important in regulating heart rate, blood pressure, and gut function. Unless drugs specific for brain receptors can be developed, therapeutic benefits are likely to be limited by the occurrence of peripheral side effects.66

Other theoretical approaches to treatment of an acetylcholine deficiency could be discussed, but it is clear that we have much to learn about the regulation of acetylcholine production in both the brain and peripheral nervous system before truly rational predictions can be made. Given the numbers of patients awaiting treatment, a concerted effort in this direction certainly seems justified.

VIII. WHY ARE CHOLINERGIC NEURONS SPECIFICALLY AFFECTED BY ALZHEIMER’S DISEASE?

This is perhaps the most important question raised by the neurochemical work of the last few years. Understanding the nature of the agent or process that causes the selective degeneration of the cholinergic neurons should allow us toprevent the disease. As yet, however, we have few clues. The most obvious candidate would seem to be a virus, for two reasons. First, viruses can specifically attack groups of neurons in the brain, the most striking example being polio, which has considerable selectivity for motor neurons. Second, a group of very rare dementias, including Creutzfeldt-Jocob Disease and Kuru, can be transmitted to animals by the injection of infected brain tissue into the animal brain. O n the other hand, there is no evidence for the presence of a virus in the brains of Alzheimer patients, and transmission experiments with Alzheimer brain tissue have been entirely unsuccessful. Another nega- tive comes from immunologic studies: in most virus infections, an immune response is mounted to attempt to fight off the invader. There is no clear sign of any immune response to the presumed virus in Alzheimer’s disease, and this also tends to suggest that we are not dealing with some kind of autoimmune phenomena.

There has been much concern about the possibility that Alzheimer’s disease can be inherited. This does appear to happen in a very few cases:

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there are families in which the disease appears to be inherited as an autosomal dominant trait. However, the vast majority of cases clearly do not have any familial background, and especially for those patients over 65, little or no increase in the incidence of the disease is found among first-order relatives. This suggests that while there may be a gene predisposing an individual to Alzheimer’s disease, other factors, perhaps viral or environmental, may be needed for the disease to develop.

IX. SUMMARY

At this time we seem to be on the verge of opening two new fields of research on Alzheimer’s disease. To treat the symptoms of this condition, an understanding of the factors regulating acetylcholine synthesis will be very important. Because of the vast amount of work on this neurotransmitter over the last 30 years, rapid progress in this area should be made. However, to truely conquer Alzheimer’s disease, we need to learn what it is that attacks and apparently destroys the cholinergic neurons. While this second point may take a little more time to unravel, the work will be both exciting and very worth while.

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The neurochemistry of Alzheimer's disease and senile dementia