Behavioral and histochemical characterization of a novel BACE Knockout x PDAPP 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

Abstract

This dissertation describes the phenotypic characterization of a BACE knockout (KO) x PDAPP transgenic mouse line, utilizing behavioral, histochemical, and pharmacologic methods. Overproduction and accumulation of the amyloid-|3 (A|3) peptide in the brain has been implicated as one of the causal factors in the development of Alzheimer's Disease (AD). Based on this concept, several transgenic mouse models have been created that overexpress human mutant Amyloid Precursor Protein (hAPP) that reproduces many of the cognitive and histopathological features of AD. Recently, the (3-site cleaving enzyme (BACE) responsible for the first proteolytic cleavage of APP has been characterized, and subsequent research has led to the propagation of BACE inhibition as a prime experimental strategy for AD therapy.Currently, there are many academic and pharmaceutical company laboratories actively engaged in developing therapeutic inhibitors of BACE for AD. However, the theoretical repercussions of BACE activity reduction have not yet been fully addressed in an in vivo model. Indeed, although overproduction of A|3 leads to neuroanatomical and cognitive pathology in human patients and animal models, lack ofA|3 may also result in deleterious cognitive effects. Examining the behavioral 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.To examine this issue a series of behavioral studies were conducted using homozygous and hemizygous BACE KO mice, PDAPP mice, and BACE KO; PDAPP lines together with relevant controls. The studies included various protocols in a cued and spatial watermaze task and detailed analysis of the occurrence of epileptiform seizures. Objective methods were used to analyse the changes in learning ability and the frequency of seizures.The results from the characterization of the BACE KO x PDAPP mouse line indicate that the absolute loss of BACE and A|3 caused profound spatial memory deficits, sometimes greater even than that of hAPP mice alone. In addition, absolute 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. In addition, these studies also support an important role for the [3-amyloid processing pathway in "normal" learning and memory processes, possibly by regulating neuronal activity levels.