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• W234348013 abstract "Alzheimer's disease (AD) is characterised neuropathologically by the presence of plaques and tangles in the brain. AD can be sub-grouped into early onset (EOAD, age of onset <65 yrs) and late onset (LOAD) forms, as well as either familial or sporadic types. A number of genes have mutations that cause the familial forms of AD. These include the amyloid precursor protein (APP) gene and the presenilin (PS) 1 and 2 genes. Also, inheritance of the apolipoprotein E epsilon4 allele confers susceptibility to the disease. Mutations in the APP and PS genes result in elevated levels of the arnyloidogenic peptide Abeta-42, found in AD plaques, which is hypothesised to initiate the disease process in affected individuals. The presenilins have also been proposed to play important roles in biological processes, such as development and apoptosis, and mutations in these genes are thought to deregulate pathways underlying these processes. In this study we investigated possible roles for these proteins in both normal and pathophysiological processes. As AD is a disease of ageing, we initially sought to determine whether there were any age-related changes in the expression of the AD-related APP, amyloid precursor proteinlike protein 2 (APLP2) and PS1 genes, in control human brain. Results (paper I) show there is no alteration in expression of these genes, indicating that the increased prevalence of AD, in the aged population, cannot be attributed to alterations in their expression during ageing. However, significant correlations were found between the expression levels of these genes, suggesting a functional relationship b etween them. Although expression of APP or the PSs, were unaltered during ageing, APP expression is known to be increased during brain injury, which may lead to increased AD production and susceptibility to AD. Activation of protein kinase C (PKC) has been shown to increase the nonarnyloidogenic processing of APP. Thus in paper II the effect of PKC activation in cells over-expressing APP was studied, results showed no difference in basal and PKC-stimulated AD production when APP is overexpressed, indicating that up regulation of alpha-secretase activity may not be a promising therapeutic target in treatment of AD. To further understand the role of the presenilins, we studied the effect of familial AD (FAD)-linked PSI mutations on apoptotic (paper III) and developmental (paper IV) mechanisms. We demonstrated that the FAD deltaexon9 and L250S PSI mutations sensitise the neuroblastoma SH-SY5Y cell line to hyper-osmotic stress-induced apoptosis. These FAD PS1 mutations were also shown to impair the rescue effect of insulin-like growth factor-I in these cells (paper III). The deltaexon9 mutation was found to have no effect on the differentiation potential of the same cell line. However, expression levels of both wild-type and mutated PS1 were highly elevated in cells induced to differentiate (paper IV). Therefore, we may conclude that although PSI is highly involved in neurogenesis, FAD mutations in this gene may not affect this process. Reductions in proteasome activity have been reported during the normal aging process, and in AD brain. Decreased proteasome activity has been reported in AD brain. Furthermore, proteasome inhibition in vitro has been shown to result in increased Abeta production. In paper V we have confirmed the increased production of AD in SH-SY5Y cells upon proteasome inhibition by lactacystin. SH-SY5Y cells transfected with the C-terminal 100 amino acids of APP were used, production of AD in these cells is therefore independent of beta-secretase activity and relies only on the activity of y-secretase. Therefore, these results implicate gamma-secretase activity in increased AD production upon proteasome inhibition. It was also shown in this paper that increased caspase-3 activity upon proteasome inhibition, is not involved in increased AD production in these cells. This thesis has therefore shown that the expression of AD genes does not change with normal ageing, but that an age-related process of reduced proteasome activity may provide a mechanism by which AD production is increased during ageing. Further insight into the normal physiology of these genes during developmental and apoptotic processes has also been established." @default.
• W234348013 created "2016-06-24" @default.
• W234348013 creator A5009056441 @default.
• W234348013 date "2004-10-08" @default.
• W234348013 modified "2023-09-27" @default.
• W234348013 title "Alzheimer´s disease-related amyloid precursor protein and presenlin genes : Normal function and pathophysiology" @default.
• W234348013 hasPublicationYear "2004" @default.
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