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An investigation into the cellular and molecular signalling events which occur in [Beta]-amyloid-treated cultured cortical neurons
Fogarty, Marie
THESIS 7763 Deposition of ?-amyloid around neurons is a neuropathological hallmark of Alzheimer?s disease. The aim of this study was to investigate the cellular and molecular mechanisms underlying ?-amyloid-mediated cell death in cultured cortical neurons. ?-amyloid evoked a differential timeframe of activation of specific isoforms of the stress- activated protein kinases, c-jun-N-terminal kinase. To delineate the respective roles of c- jun-N-terminal kinase iso forms in ?-amyloid-mediated cell death, antisense oligonucleotide technology was used. The results demonstrate that c-jun-N-terminal kinase 1 is the principal isoform involved in ?-amyloid-mediated activation of caspase-3 and DNA fragmentation. c-jun-N-terminal kinase 1 also stabilised the tumour suppressor protein, p53, via phosphorylation at serine-15. The p53 inhibitor, pifithrin-a, reduced the ?-amyloid-mediated increase in expression of pro-apoptotic Bax, activation of caspase-3, cleavage of the DNA repair enzyme, poly (ADP) ribose polymerase, and subsequent DNA fragmentation, indicating that P-amyloid, at least in part, arbitrates neuronal cell death in a p53-dependent manner. ?-amyloid increased Bax and p53 expression at the mitochondria. The increased mitochondrial association of Bax and p53 coincided with release of mitochondrial cytochrome c to the cytosol suggesting that these proteins play a role in ?-amyloid-mediated regulation of the mitochondrial membrane. A particularly exciting discovery was the observation that ?-amyloid promoted the association of Bax and p53 with lysosomes. The association of these proteins with lysosomes coincided with an alteration in lysosomal integrity. Pifithrin-a attenuated the ?-amyloid -mediated increase in cytosolic activity of the lysosomal protease, cathepsin-L, suggesting a novel mechanism whereby p53 may contribute to destabilisation of lysosomal membranes and promote leakage of lysosomal constituents.
Keyword(s): Physiology, Ph.D.; Ph.D. Trinity College Dublin
Publication Date:
2004
Type: Doctoral thesis
Peer-Reviewed: Unknown
Language(s): English
Institution: Trinity College Dublin
Citation(s): Marie Fogarty, 'An investigation into the cellular and molecular signalling events which occur in [Beta]-amyloid-treated cultured cortical neurons', [thesis], Trinity College (Dublin, Ireland). Department of Physiology, 2004, pp 350
Publisher(s): Trinity College (Dublin, Ireland). Department of Physiology
Supervisor(s): Campbell, Veronica
First Indexed: 2016-12-17 07:26:28 Last Updated: 2019-10-04 07:03:36