Characterising transgenic APP mutation mouse models of amyloid pathology for use in preclinical immunotherapy
Year: 2012
Type: dissertation
Abstract: No disease-modifying compounds are available to halt disease progression in Alzheimer’s \ndisease (AD). Immunotherapy offers promising possibilities for the manipulation of Aβ levels \nwhich 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 \nthe β-secretase cleavage site of the amyloid precursor protein (APP) from which Aβ is cleaved \nhas been shown to downregulate Aβ in human cell lines. The approach is thought unlikely to \ncause inflammation as the immune system is not relied upon for Aβ clearance. It was \nhypothesised that the administration of 2B3 to aged transgenic APP mutation mice would \nlower Aβ levels through the inhibition of Aβ production, with an associated lowering of \ncognitive deficits. Two murine APP mutation models [London APP(V717I) and Indiana \nPDAPP(V717F)] were characterised in order to identify cognitive deficits against which the \nability of 2B3 to reduce deficits could be assessed. APP(V717I) mice were assessed in the \nmarble burying task, the elevated plus maze and a foraging task assessing spatial working \nmemory at 3, 6 and 19 months of age. The radial arm water maze was carried out at 10 \nmonths, before the T-maze non-matching to position task was administered at 11 months. \nObject recognition memory was assessed at 18 months. Similarly, PDAPP mice were assessed \nusing the marble burying and elevated plus maze (9.5months), the T-maze (9-10 months), the \nforaging task (11 and 14 months) and the object recognition task (12 months). Whilst aged \ntransgenic PDAPP mice displayed disrupted spatial working memory, no evidence of agerelated cognitive decline was observed in APP(V717I) transgenic mice despite increases in Aβ \npathology with age. 2B3 did not alter Aβ levels or spatial working memory in PDAPP(V717F) \nmice in a pilot study, whilst the in vitro downregulation of Aβ was successfully replicated in \nprimary murine neurons. The findings indicate that transgenic models of neurodegenerative \ndisease require thorough characterisation to optimise their use in pre-clinical research. \nFurthermore, the use of alternative immunotherapy in the treatment of AD remains a \npromising, but early stage avenue of study.
Author: Martha Hvoslef‐Eide
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1627873551