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Title: Messenger RNA studies in Alzheimer's disease
Author: Wighton-Benn, Wendy Helen
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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In this thesis, in situ hybridisation histochemistry was the principal technique applied to the study of a number of specific species of messenger RNA (mRNA) in tissue from normal and diseased post-mortem human brains. Gs and Go are members of the heterotrimeric G protein family whose members are crucial to cellular responsiveness. APP and Goa mRNA levels were found to be reduced in the dentate gyrus of AD sufferers in comparison to controls and were positively correlated in this region irrespective of diagnosis. The APP gene is encoded on chromosome 21 and APP mRNA levels are increased in Down's syndrome in keeping with the 50% increase in gene dosage associated with trisomy 21 (Tanzi et al. 1987). Increased APP mRNA levels are postulated to be responsible for the early appearance of the pathological stigmata of AD in individuals with this condition. However, a comprehensive analysis of APP mRNA levels in the hippocampus and visual cortex of diseased and control brains concluded that increased APP mRNA levels are not a feature of AD. An increase in the ratio of potentially amyloidogenic KPI-encoding, relative to KPI-lacking, APP mRNA transcripts was documented with age in the visual cortex of diseased and control brains. Further, the major determinant of this ratio differed between the visual cortex and the hippocampus. Ubiquitin is a highly conserved member of the heat shock protein family essential to ATP-dependent non-lysosomal proteolysis. Ubiquitin mRNA, when expressed as a proportion of polyadenylated mRNA, was increased in the visual cortex of individuals diagnosed as suffering from borderline AD in comparison to the other diagnostic groups studied. The implications of the above findings in relation to the pathogenesis of AD and the challenges inherent in the application of biomedical research techniques to the study of a uniquely human disease like AD, using human post-mortem brain tissue, are discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available