Second Messenger Systems in Alzheimer's Disease: A Quantitative Autoradiographic Study

Horsburgh, Karen J (1990) Second Messenger Systems in Alzheimer's Disease: A Quantitative Autoradiographic Study. PhD thesis, University of Glasgow.

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Abstract

Quantitative ligand binding autoradiography was used to map key components of second messenger systems in the CNS. [3H]-Forskolin binding to Gs-adenylate cyclase and [3H]-phorbol 12,13 dibutyrate (PDBu) binding to protein kinase C was investigated in human postmortem brain of control patients and patients with Alzheimer's Disease (AD). Disruption of glutamatergic and cholinergic systems may contribute to the pathology of AD. In view of this, alterations in ligand binding sites following selective lesions of glutamatergic and cholinergic pathways in rat brain were used as a framework on which to elucidate possible plastic modifications of second messenger systems in AD. Since the primary lesion in AD occurs within the cortex, ligand binding to second messenger systems was investigated following excitotoxic lesion of the rat cerebral cortex. Second Messenger Ligand Binding in Alzheimer's Disease:In two separate series, [3H]-forskolin binding was investigated in a total of 15 controls and 16 age-matched patients dying with AD in middle frontal and temporal cortices and in the hippocampal formation. AD brains contained numerous neuritic plaques in both cortical areas and the hippocampal region, whilst controls had minimal neuritic plaques. Choline acetyltransferase (ChAT) activity was significantly reduced (>50%) in AD compared to control subjects in both cortex and the hippocampus. [3H]-Forskolin binding was significantly reduced by approximately 50% in all layers of the middle frontal cortex in AD brain compared to controls. There was a positive correlation between [3H]-forskolin binding and ChAT activity in each layer of frontal cortex (correlation coefficient, r = 0.662 - 0.712) when data from control and AD brain were combined. [3H]-Forskolin binding was minimally altered in 1 of the 11 discrete regions examined in the hippocampus in AD brain compared to control. ChAT activity and [3H]-forskolin binding were unrelated in any region of the hippocampus (r = 0.42 - 0.6). In the temporal cortex and the molecular layer of the dentate gyrus, there was evidence that [3 H]-forskolin binding was lower in AD patients compared to control subjects. Whether these changes achieved the probability level of 5% was a reflection of group size, variability of measurements, and the errors of sampling heterogeneous populations. There was no association between the number of neuritic plaques and [3H]-forskolin binding in any brain region examined. The effect of 5'guanylimidodiphosphate (Gpp(NH)p) on [3H]-forskolin binding was examined in adjacent sections from the same group of control and AD patients. In control brain, basal levels of [3H]-forskolin binding were significantly increased in layers I-III of middle frontal cortex (28%) and middle temporal cortex (30%) in the presence of Gpp(NH)p. In AD brain, the ability of Gpp(NH)p to enhance [3H]-forskolin binding from basal levels in cortical layers (I-III) was conserved. Gpp(NH)p had no effect on the level of [3H]-forskolin binding within each region of the hippocampus in the control or AD group. In a separate study, both quantitative autoradiography and homogenate binding to particulate and cytosolic fractions were employed to investigate [3H]-PDBu binding in middle frontal and temporal cortices, and the hippocampal region of nine control and nine AD subjects. All AD brains exhibited extensive signs of the pathology classically associated with the disease, namely numerous neuritic plaques and a profound reduction in ChAT activity ( 60%) in both cortical areas and the hippocampus. Quantitative autoradiographic analysis of [3H]-PDBu binding showed there was no significant difference between control and AD sections in all areas examined within the middle frontal and temporal cortices and hippocampal formation. In adjacent sections to those used for [3H]-PDBu autoradiography, [3H]-forskolin binding was markedly reduced in all layers of middle frontal and temporal cortex (at least 30%) and in the molecular layer of the dentate gyrus (38%) in AD when compared with control subjects. In a parallel study, [3H]-PDBu binding to homogenate preparations of control and AD brain confirmed that there was no significant difference in [3H]-PDBu binding in either the particulate or cytosolic fraction. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Neurosciences
Date of Award: 1990
Depositing User: Enlighten Team
Unique ID: glathesis:1990-78229
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Feb 2020 12:09
Last Modified: 28 Feb 2020 12:09
URI: http://theses.gla.ac.uk/id/eprint/78229

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