Steele, Janet Elizabeth; (1990) Cortical neurones in Alzheimer's disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Two major neurotransmitter systems, cholinergic and glutamatergic, have been studied, mainly in the cortex of patients with Alzheimer's disease. Choline acetyltransferase (ChAT) activity was assayed in 15 areas of the cerebral cortex taken post-mortem from patients with Alzheimer's disease and controls. The number of neurofibrillary tangles was determined in an adjacent tissue sample. ChAT reduction and tangle numbers were maximal in structures of the medial temporal lobe (the uncus, amygdala, hippocampus and parahippocampal gyrus), severe in the neocortex on the lateral surface of the temporal lobe, moderate in the association cortex of the cortex of the parietal and frontal lobes and minimal in the primary somatic and visual sensory areas. These results are interpreted as providing support for the hypothesis that the pathological process in Alzheimer's disease may spread along a sequence of cortico-cortical connections between the main sensory area and the hippocampal formation. Earlier work in this laboratory suggested that glutamatergic neurones are involved in this process. Furthermore, tangles appear to be localized in pyramidal cells which probably use glutamate as their transmitter. Due to a lack of a suitable enzyme marker for glutamatergic cells, this type of cell is extremely difficult to investigate in humans. A drug with possible efficacy in Alzheimer's disease has been examined for effects on glutamatergic neurones (using laboratory animals). In addition a glutamate receptor subtype has been studied in detail, using post-mortem human tissue. Tetrahydro-9-aminoacridine (tacrine), an alleged drug for the treatment of Alzheimer's disease was examined for effects on glutamatergic neurones in rat brain. The Ca2+-dependent release and Na+-dependent uptake of amino acids in tissue prisms were inhibited by the drug. Extracellular amino acid concentrations (collected by in vivo microdialysis and measured by HPLC with fluorometric detection) were elevated by the drug. However, none of these effects were observed with concentrations thought to be clinically relevant suggesting that the alleged clinical benefit is dependent on the well documented cholinomimetic actions of this drug. The binding of [3H]-(+)-5-methyl-10 ,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10 imine maleate [3H]-MK-801) and [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine [3H]- TCP) to the N-methyl D-aspartate (NMDA) receptor complex were studied in control post-mortem human brain taken from all cortical areas which was pooled before study. Binding of both ligands was stimulated by glutamate and glycine but the addition of both glutamate and glycine together resulted in an additional effect on [3H]-MK-801 binding only. Saturation analysis revealed approximately twice as many high affinity sites for [3H]-MK-801 than for [3H]-TCP binding. Cortical tissue from the temporal lobe, a severely affected area in Alzheimer's disease, and the frontal lobe, moderately affected, from a number of patients were assayed by radioligand binding for the density of the NMDA receptor complex using [3H]-MK- 801 and [3H]-TCP binding. There did not appear to be an alteration in the density of this receptor in Alzheimer's disease in the temporal cortex but there was a decrease in [3H]-MK-801 binding in the frontal cortex. The modulation of the NMDA receptor complex by glutamate, glycine, zinc and a polyamine, was examined in post-mortem human brain. In control brain the modulation by all four substances was similar to that in rat brain indicating that the NMDA receptor complex is similar in rat and human brain. In Alzheimer's disease tissue, there appeared to be a selective impairment of regulation by glycine and spermidine. These data are discussed in terms of a starting point for rational pharmacotherapy for Alzheimer's disease.

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