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The role of CBP and p300 in Alzheimer's disease

Francis, Y.I.; (2008) The role of CBP and p300 in Alzheimer's disease. Doctoral thesis, UCL (University College London).

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Abstract

Studies of the mechanisms underlying memory formation have defined central roles for CRE-dependent gene expression, which is mediated by the transcription factor CREB and the coactivator CBP. CBP creates a bridge between CREB and the basal transcriptional machinery and acetylates histones, which induces chromosomal changes and results in loss of chromosomal repression. This allows successful transcription of the underlying genes needed for synthesis of proteins underlying memory formation. CBP has been linked to neurodegenerative diseases and cerebral CBP levels were shown to reduce in mice lacking functional presenilins (PSs), a class of enzymes that has been associated with Alzheimer’s disease (AD). In this thesis it is shown that WT PS1 stimulates the transcriptional activating ability of CBP and its close homolog p300, whereas an Alzheimer’s disease- associated N terminal mutant of PS1 did not produce this effect. Interestingly, PS1 C terminal mutants produced a reduction in CBP transcriptional activating ability, compared to control levels. Additionally, we showed that wild type PS1 increases the endogenous CBP level. Moreover, an increase in CBP endogenous levels was noted when the cells were transfected with the -M146L N-terminal mutant of PSI. However, these levels were still significantly lower when compared to cells transfected with wild type PS1. We were also able to show that knockdown of endogenous PS1 leads to a decrease in endogenous CBP levels and a decrease in CBP activity. Hence, PSI can affect both the level and the activity of CBP. In addition, the activation of CBP by WT PS1 involves the PI 3-kinase, p38 MAP kinase and p42/p44 MAP kinase pathways and targets primarily the C terminus of CBP. It is also shown that the effect of wild-type PS1 is dependent on the histone acetyltransferase activity (HAT) of CBP. Moreover, it was demonstrated that WT PS1, but not its M146L mutant, could increase the promoter activity of c-fos, a CBP HAT dependent target gene. Additionally, we showed that application of the histone deacetylase inhibitor, TSA, rescued the long-term potentiation and long-term memory defects shown by APP/PS1 mutant mice. Moreover, it was shown that the acetylation level of histone H4 in APP/PS1 mice is lower than that of WT littermates and that TSA injection restores the acetylation of these histones. This is the first study to identify AD as a disease of epigenetic etiology and suggests that enhancing histone acetylation may have potential for the treatment of AD.

Type:Thesis (Doctoral)
Title:The role of CBP and p300 in Alzheimer's disease
Language:English
Additional information:Authorisation for digitisation not received
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Genes, Development and Disease > ICH - Medical Molecular Biology Unit

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