Neurobiological, neurobehavioural and metabolic correlates of Alzheimer's Disease in mouse models
Beta-site APP Cleaving Enzyme 1 (BACE1) is a key enzyme in the generation of P-amyloid, the major component of senile plaques in the brains of Alzheimer's Disease patients. Transgenic mice carrying human BACE1 cDNA and knockout mice with endogenous murine BACE1 removed were tested for behavioural, neurochemical and physiological changes with respect to appropriate wild type control mice. BACE1 transgenic mice exhibited a bold, exploratory behaviour, showed elevated 5-HT turnover and had unimpaired cognition. BACE1 knockout mice showed a contrasting behaviour, being timid and less exploratory with sex-dependent memory impairment as measured in the fear conditioning test. Unexpectedly these mouse lines did show alterations in their ability to put on weight suggesting an intriguing link between BACE1 and fat metabolism. Despite these clear differences both mouse lines were viable and fertile with no changes in morbidity. The behaviour of a mouse line with both BACE1 and BACE2, a homologue of BACE1, endogenous genes knocked out was also investigated. The added deletion of endogenous BACE2 had no additional effect beyond that seen in BACE1 knockout mice. Compound transgenic mice carrying human BACE1 and Swedish mutant Amyloid Precursor Protein (APPkm67o/67inl) transgenes or human mutant Presenilin 1 (PS1mi46v) and APPkm67o/67inl transgenes were tested for cognitive deficits. In combination with APPkm67o/67inl, the presence of the BACE1 transgene had no effect on cognition but the presence of the PS1mi46v transgene did result in impaired learning and memory. The results presented in this thesis suggest an unexpected role for BACE1 in neurotransmission and fat metabolism, perhaps through changes in APP processing and 3-amyloid levels although these effects may be unrelated to the role of BACE1 as p-secretase. As BACE1 inhibition is a target for Alzheimer's Disease modification, the potential effect of BACE1 therapeutic agents on anxiety and cognition should be considered.