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Characterising transgenic APP mutation mouse models of amyloid pathology for use in preclinical immunotherapy

Hvoslef-Eide, Martha 2012. Characterising transgenic APP mutation mouse models of amyloid pathology for use in preclinical immunotherapy. PhD Thesis, Cardiff University.
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No disease-modifying compounds are available to halt disease progression in Alzheimer’s disease (AD). Immunotherapy offers promising possibilities for the manipulation of Aβ levels which the amyloid cascade hypothesis proposes as the causative factor in AD. However, antiAβ antibodies have caused inflammation in vivo. An alternative antibody (2B3) which targets the β-secretase cleavage site of the amyloid precursor protein (APP) from which Aβ is cleaved has been shown to downregulate Aβ in human cell lines. The approach is thought unlikely to cause inflammation as the immune system is not relied upon for Aβ clearance. It was hypothesised that the administration of 2B3 to aged transgenic APP mutation mice would lower Aβ levels through the inhibition of Aβ production, with an associated lowering of cognitive deficits. Two murine APP mutation models [London APP(V717I) and Indiana PDAPP(V717F)] were characterised in order to identify cognitive deficits against which the ability of 2B3 to reduce deficits could be assessed. APP(V717I) mice were assessed in the marble burying task, the elevated plus maze and a foraging task assessing spatial working memory at 3, 6 and 19 months of age. The radial arm water maze was carried out at 10 months, before the T-maze non-matching to position task was administered at 11 months. Object recognition memory was assessed at 18 months. Similarly, PDAPP mice were assessed using the marble burying and elevated plus maze (9.5months), the T-maze (9-10 months), the foraging task (11 and 14 months) and the object recognition task (12 months). Whilst aged transgenic PDAPP mice displayed disrupted spatial working memory, no evidence of agerelated cognitive decline was observed in APP(V717I) transgenic mice despite increases in Aβ pathology with age. 2B3 did not alter Aβ levels or spatial working memory in PDAPP(V717F) mice in a pilot study, whilst the in vitro downregulation of Aβ was successfully replicated in primary murine neurons. The findings indicate that transgenic models of neurodegenerative disease require thorough characterisation to optimise their use in pre-clinical research. Furthermore, the use of alternative immunotherapy in the treatment of AD remains a promising, but early stage avenue of study.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology
Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Funders: Alzheimer's Society UK
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:13

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