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Investigating the role of normal and abnormal beta-amyloid processing in cognition

Freeman, Thomas James 2019. Investigating the role of normal and abnormal beta-amyloid processing in cognition. PhD Thesis, Cardiff University.
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Alzheimer’s Disease (AD) affects over 30 million people worldwide, however no disease modifying therapies have been approved to date. The majority of failed therapeutic intervention targeted the accumulation of beta-amyloid (Aβ) species. While these interventions were effective in preclinical mouse models of early stage amyloid pathology they failed to translate into the clinic. While several explanations may underlie this apparent lack of translation, one commonly held view is that first generation mouse models possess artefacts that contribute to brain and cognitive phenotypes. Another factor that has not received detailed consideration is the extent to which reduction of endogenous amyloid production influences cognition and synaptic processes in cognitively normal mice. This thesis aimed to elucidate the role of Aβ in cognitive function in both wild-type (WT) mice and a novel single knock-in mouse APP-NL-F mouse model of pre-symptomatic amyloid pathology. Selective inhibition of Aβ production was achieved by using the 2B3 antibody, which binds to the β-cleavage site of the amyloid precursor protein (APP), sterically inhibiting metabolism. 2B3 administration significantly reduced Aβ and altered glutamate receptor dynamics in the hippocampus of 5-month old WT mice following icv (intracerebroventricular) infusion. These mice failed to detect changes in object-in-place (OiP) associations, confirming that hippocampal Aβ was required for this cognitive task. APPNL-F knock-in mice express a humanised Aβ sequence with the Swedish (KM670/671NL) and Iberian (I716F) mutations within the endogenous murine APP gene. These mice underwent behavioural characterisation at 8 and 17 months of age and this revealed a pattern of selective memory deficits that were age-dependent. This included an age-dependent deficit in a foraging-based spatial working memory task and deficits in both associative OiP and temporal order recognition memory. 2B3 infusion in aged WT and APPNL-F mice reduced Aβ production but resulted in dissociable effects on memory. A deficit in OiP performance was rescued by 2B3 administration in APPNL-F mice but performance was impaired in healthy WT controls. These data provide novel evidence for the importance and dynamic role of Aβ in both normal and early stage AD pathology. One implication of these findings is that, should anti-amyloid therapies gain traction in the treatment of pre-symptomatic AD, the benefits must be weighed against the potential adverse effect of disrupting normal amyloid function.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology
Funders: Wellcome Trust
Date of First Compliant Deposit: 14 February 2020
Date of Acceptance: 13 February 2020
Last Modified: 14 Feb 2020 10:34

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