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Title: Behavioural and histochemical characterisation of a novel BACE knockout xPDAPP mouse model of Alzheimer's disease : examination of potential effects of BACE inhibition on Alzheimer's disease and the role of APP, Aβ and BACE in normal and pathological memory function
Author: Kobayashi, D. T.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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This dissertation describes the phenotypic characterisation of a BACE knockout (KO) x PDAPP transgenic mouse line, utilising behavioural, histochemical, and pharmagologic methods. Several transgenic mouse models have been created that overexpress human mutant Amyloid Precursor Protein (hAPP) that reproduced many of the cognitive and histopathological features of AD. Recently, the β-site cleaving enzyme (BACE) responsible for the first proteolytic cleavage of APP has been characterised, and subsequent research has led to the propagation of BACE inhibition as a prime experimental strategy for AD therapy. Examining the behavioural and histological phenotypes of BACE KO animals on normal and hAPP overexpressing backgrounds is an effective way to assess whether the inhibition of BACE is a reasonable strategy for the treatment of AD. Behavioural studies were conducted using homozygous and hemizygous BACE KO mice, PDAPP mice, and BACE KO: PDAPP lines together with relevant controls. The results form the characterisation of the BACE KO x PDAPP mouse line indicate that the absolute loss of BACE and Aβ caused profound spatial memory deficits, sometimes greater even than that of hAPP mice alone. BACE KO was associated with spontaneous seizures as well as greater seizure activity in drug-induced seizure experiments. However, the partial hemizygous deletion of the BACE gene on a hAPP background appeared to improve spatial memory performance on certain measures and protect against drug-induced seizure responses relative to hAPP mice. The research described in this dissertation is consistent with the notion that, under certain circumstances, therapeutic inhibition of BACE may prove to be a valuable strategy for treatment of AD. These studies also support an important role for the APP processing pathway in “normal” learning and memory processes, possibly by regulating neuronal activity levels.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available