6. The cholinergic system and the excitatory amino acids in Alzheimer’s disease

David Bowen Miriam Marks Department of

Neurochemistry, Institute of Neurology, University of London, 1 Wakefeld St.,

London WCIN 1PJ. UK

The application in the 1960s of methods of biochemical analysis to human samples led to important advances in the understanding of brain diseases, particularly the inborn errors of lipid metabolism and Parkinson’s disease. Later, when large reductions in choline acetyl- transferase (ChAT) in the cortex were identified and the cholinergic nature of some basal forebrain neurones were described, an appreci- ation of the potential importance to therapy of biochemical analyses of Alzheimer’s (AD) brain tissue began to develop.

The prospect of obtaining meaningful data from diseased postmortem brain may be questioned as parameters under scrutiny may be influenced by factors such as immediate pre- terminal status (sudden death or prolonged coma), drug history and tissue atrophy. Interpretation of data therefore requires fastidi- ous consideration of a number of factors in order to separate changes that are due to brain disease from those that occur as a result of epiphenomena. It is difficult to identify changes occurring early in AD by examination of tissue obtained from postmortem, where the disease has usually run its full course. Thus small amounts of brain tissue, removed for diagnostic purposes, have also been used for biochemical analyses, an approach pioneered by the late Saul Korey. The samples offered to the author (39, between 1976 and 1987) from seven U.K. centres have contributed to the knowledge of the biochemistry of AD.

Firstly, it has helped to separate disease- related change from the artefact and the epi- phenomena normally associated with post-

mortem tissue (e.g. problems associated with terminal coma). Secondly, it has allowed firmer conclusions to be drawn about neuronal integrity by permitting assessment of a variety of biochemical markers for a single neurone type. Thirdly, it has provided some insight into the neuronal changes that occur early in the disease, and, together with postmortem data, changes that occur at a later stage. Finally, biochemical measures assessed antemortem in this laboratory have the advantage that there has been a fixed and short duration (< 2 weeks) between neuropsychological assessment and the removal of tissue. Moreover, detailed clinico- pathological assessments have been made, including a rating of the magnitude of dementia from a number of tests that assessed the extent of the following clinical domains: memory, perceptuwspatial abilities and language. The rating correlated with acetylcholine synthesis but not with other cortical transmitters (noradrenaline, dopamine and serotonin, 5-HT) and gamma-aminobutyric acid (GABA) was apparently increased or unaltered. Loss of pyramidal neurones may be a critical change since atrophy - corrected counts of such cells in cortical layers I11 and V of the same subjects were found to correlate with the magnitude of dementia. Korey described “a decrease in the glutamic acid group”, which is confirmed. The most straight-forward interpretation of this finding is that glutamatergic neurones as well as cholinergic nerve endings are lost from the cerebral cortex in AD.

Cholinergic and glutamatergic neurones are the major corticopetal and intrinsic cortical

15

30WEN

Somatostatin 5-HT receptor protein

uptake

. CABA

D-3H-ASP uptake ASP

I 5-HT

15-21 22-24 > 24 0

ns

% Reduction (1 8F) FI uorod eoxyg I ucose uptake

Figure 6.1. Evidence of selective changes in the parieto- temporal lobes in Alzheimer‘s disease based on postmortem (A) and antemortem (B) biochemical measurements expressed per unit mass or volume, except for protein per area. A, identifies the Brodmann Area that shows the most severe reduction of each measure (8 areas were assayed as shown by numbers). B, is calculated from published values of other workers.

neurones, respectively, and both have been implicated by animal studies in learning and memory. Neuropeptides, such as somatostatin, are associated with only 5-10 per cent of cortical neurones and losses are not obvious in the biopsy samples or in some cortical regions assayed postmortem, except in series that included only pathologically severe examples of the disease. Detailed neurotransmitter studies of various cortical (Brodmann) areas from post- mortem brain have complemented results obtained by histological and in vivo brain imaging techniques by identifying selective cholinergic and glutamatergic dysfunction with- in the parietotemporal lobes, as shown in Figure 6.1.

AD appears to be genetically heterogenous so treatments inde- pendent of gene identification are re- quired. Cholinergic and glutamatergic dysfunction should provide a focus for those interested in providing symptomatic treatment. Tacrine (1,2, 3,4-tetrahydro-9-aminoacridine) is an effective acetylcholinesterase inhi- bitor and preliminary studies tenta- tively suggest some therapeutic efficacy in AD. Clinically relevant concentrations of the drug are un- likely to either produce harmful (neurotoxic) effects of the excitatory amino acids or to directly affect glutamatergic neurotransmission. Be- cause disruption of this neuro- transmission system could possibly produce some of the symptoms of AD, treatment with glutamate agonists might theoretically be of benefit. This could be potentially quite dangerous so the glycine modulatory domain of the N-methyl- D-aspartate/phencyclidine receptor complex, rather than the primary agonist site, is probably the preferred locus for any attempt to correct glutamatergic dysfunction.

References

Bowen, D.M., Francis, P.T., Lowe, S.L., Pangalos, M.N., Procter, A.W. and Steele, J.E. ‘Pyramidal neuron loss and “glycine-site therapy”: A need for an animal mode and study. in late-life depression’, Neurobiol. Aging 1989: 10 14-16. Francis, P.T. and Bowen, D.M. ‘Tacrine, a drug with therapeutic potential for dementia: Postmortem biochemical evidence’, Can. J . Neurol. Sci. 1989: 16: no. 3 (in press). MaCabe, B.J. and Horn, G . ‘Learning and memory: Regional changes in N-methyl-D-aspartate receptors in the chick brain after imprinting’, Proc. Nutl. Acad. Sci. 1988 (USA): 85: 2849-55.

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