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Title: Neuropathological and molecular analyses of a transgenic mouse model over-expressing a C-terminal fragment of human familial Alzheimer's disease APP
Author: Choudhury, S. K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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The study began with further neuropathological characterisation of a novel transgenic mouse model (APP-CT100 [V7171]) over-expressing, in neurons, a human carboxy-terminal fragment of APP (CT100) with the FAD [V7171] mutation. In theory, the [V7171] mutation gives rise to increased levels of the longer, pathologic amyloid-beta peptide (Aβ42) and the accumulation of the carboxy terminal fragment of APP, AICD. Immunohistochemical analysis revealed that human Aβ40 was detected both extracellularly as diffuse-like deposits and intracellularly in the cortex and hippocampus, whereas human Aβ42 was predominantly deposited extracellularly in the parenchyma and in capillaries. Moreover, both Aβ40 and Aβ42 pathologies appeared to increase with age. Further, immunohistochemical and Western blot analyses demonstrated an age-related astrogliosis response associated with the Aβ40 and Aβ42 deposits. In conclusion, these findings suggest the APP-CT100 [V7171] mouse modelled certain neuropathological features of FAD. Multiple lines of evidence support pivotal roles for CT100 and its metabolites (i.e. Aβ and AICD) in AD synaptic dysfunction and neuronal cell death by apoptosis. However, the underlying molecular basis of this is still not fully understood. Furthermore, it has been difficult to show apoptosis in animal models of AD and indeed in human AD brains. In the second and third parts of this study, an alternative approach was used to address this issue, whereby the upstream regulators of apoptosis (e.g. Akt, MAPKs, CREB and members of the Bcl-2 family) were examined with the aim of identifying changes, presumably reflecting neurons in the early stages of apoptosis. Thus in the second part of this project, the age-related effects of the APP-CT100 [V7171] transgene on the major signalling pathways regulating survival and apoptosis, namely Akt, ERK1/2, JNK and p38 were examined in pathologic (cortex and hippocampus) and control brain regions in 3, 6, 12 and 24 month old cognitively assessed mice. Changes in kinase activity were monitored by Western blot analysis of the phosphorylation status of these effectors. There was an early impairment of neuroprotective pathways and later up-regulation of stress-apoptotic pathways in the pathogenic brain regions. Interestingly, ERK1/2 and CREB are involved in molecular processes underlying learning and memory. The hypo-activation of ERK1/2 and CREB before the onset of olfactory memory deficit in memory-related areas, the cortex and hippocampus, suggest impairment in their roles in memory and/or survival signalling may contribute to the observed cognitive decline in the APP-CT100 [V7171] mouse. The final part of the study investigated the impact of the age-dependent dysregulation of cell survival and cell death signalling effectors on the expression of pro-survival, pro-apoptotic and pro-inflammatory genes in the cortex, using semi-quantitative Taqman RT-PCR analysis. Expression of anti-apoptotic genes was down-regulated in young animals, whilst expression of pro-apoptotic and pro-inflammatory genes was up-regulated in older animals.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available