Microtubule-Associated Protein Tau in Oligodendrocytes Following Acute Brain Injury

Irving, Elaine Alison (1996) Microtubule-Associated Protein Tau in Oligodendrocytes Following Acute Brain Injury. PhD thesis, University of Glasgow.

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With the growing evidence supporting glia-neuronal signalling it is becoming increasingly apparent that it is crucial to gain an understanding of the mechanisms underlying the degeneration of both neurons and glia to fully understand the pathogenesis of acute and chronic degenerative diseases of the brain. Breakdown of the cytoskeleton is thought to represent a common pathway mediating irreversible neuronal damage in a variety of both acute and chronic neurodegenerative conditions. One of the most well documented alterations to the cytoskeleton, occurring in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and progressive supranuclear palsy, is the formation of neurofibrillary tangles. The formation of neurofibrillary tangles is thought to involve alterations in the microtubule-associated protein tau, the protein being hyperphosphorylated compared to its normal form. Tau is traditionally believed to be a neuron-specific protein where it is predominantly located within the axonal compartment. Supporting this specific localisation of tau, immunoreactivity was found only within axons in histologically normal rat or human brain tissue throughout the investigations carried out in this thesis. However, the novel finding of this thesis was the presence of tau immunoreactivity within oligodendrocytes in both rat and human brain tissue following acute brain injury. The studies described in this thesis were aimed at characterising the increased tau immunoreactivity present in oligodendrocytes in animal models of acute brain injury, in human post-mortem brain tissue from patients who died following a stroke or head injury and in an oligodendrocyte cell line. In the initial study of the thesis tau-positive oligodendrocytes were present 4 h following glutamate-induced toxicity in the rat. In order to confirm that the induction of tau immunoreactivity in these cells following injury was not a phenomenum characteristic to the rat, human post-mortem brain tissue from acute brain injured patients was examined for the presence of tau-positive oligodendrocytes. Tau-positive oligodendrocytes were detected within areas of tissue, as defined by decreased haematoxylin and eosin staining, affected by brain injury, but not in tissue obtained from control patients who had no previous history of neurological or psychiatric disorders. Tau-positive oligodendrocytes were detected as early as 2 h following head injury, suggesting that this is a rapid response of these cells to acute brain injury. In support of this, the induction of tau immunoreactivity in oligodendrocytes was detected as early as 40 min following the induction of permanent focal cerebral ischaemia in the rat. Glutamate toxicity has been shown to be involved in neuronal degeneration following ischaemic brain injury, and tau-positive oligodendrocytes were detected 4 h following intracortical perfusion of IM monosodium glutamate, both within the resulting cortical lesion and in the white matter immediately underlying this area. This result implicated glutamate in the mechanisms underlying the accumulation of tau in oligodendrocytes following injury. However, the ability of NaCl to induce a similar response in oligodendrocytes suggested that mechanisms other than glutamate toxicity may be involved. Using pure oligodendrocyte cultures exposed to monosodium glutamate or NaCl it was shown that alteration of tau in these cells was a direct effect, not mediated through neuronal degeneration. Taken together the results of these studies indicated that some aspect of the brain injury in vivo other than glutamate receptor activation may be involved in the alteration of tau in oligodendrocytes. In order to investigate further the mechanisms which may be involved in this oligodendrocyte response, the effects of 3 pharmacological agents on the density of tau-positive oligodendrocytes following focal cerebral ischaemia in the rat were determined. Pre-treatment with the spin trap agent alpha-phenyl-tert-butyl-nitrone reduced the number of tau-positive oligodendrocytes by 55% in the subcortical white matter of the ischaemic hemisphere compared to untreated animals at 40 min after middle cerebral artery occlusion. In contrast, pre-treatment with glutamate receptor antagonists dizocilpine or 2,3-dihydroxy-6-nitro-7-sulpfamoyl-benzo(F) quinoxaline, failed to reduce the number of tau-positive oligodendrocytes following 40 min of ischaemia. Thus free radial mediated mechanisms were involved in the induction of tau immunoreactivity in oligodendrocytes following ischaemic brain injury. In both the animal models of brain injury and the human post-mortem brain tissue obtained from patients who died following a stroke or head injury, tau-positive oligodendrocytes were detected with a range of antibodies to different epitopes of the protein. This suggested that there may be increased levels of the full-length protein. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Deborah Dewar
Keywords: Neurosciences
Date of Award: 1996
Depositing User: Enlighten Team
Unique ID: glathesis:1996-75308
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 21:15
Last Modified: 19 Nov 2019 21:15
URI: http://theses.gla.ac.uk/id/eprint/75308

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