Temporal Effects of Neuron-specific beta-secretase 1 (BACE1) Knock-in on the Mouse Brain Metabolome: Implications for Alzheimer's Disease.

Beta secretase 1 (BACE1) is an enzyme involved in the pathogenesis of Alzheimer's disease (AD). PLB4 mice are a neuron-specific human BACE1 knock-in mouse model characterized by the accumulation of extracellular Aβ and an AD-like phenotype. In this investigation brain hemispheres from 'young' (4-6 months) and 'old' (8 months) female PLB4 mice and age-matched wild-type littermates underwent targeted LC-MS/MS metabolomic profiling. Powdered lyophilized brain tissue was extracted in ethanol:PBS 85%:15% (v/v)) and a total of 187 metabolites were quantified using a targeted metabolomics methodology. Multivariate statistical analysis produced models distinguished PLB4 from wild type (WT) mice regardless of their age group. Univariate analysis (t-test) found that more brain metabolites were perturbed in 'old' PLB4 mice than 'young'. Carnosine and 8 phosphatidylcholine species were significantly decreased (p < 0.05) in 'young' PLB4 mouse brain. In 'old' PLB4 mice a total of 21 metabolites were perturbed including: leucine, creatinine, putrescine and species of acylcarnitines, lysophosphatidylcholines, phosphatidylcholines and sphingomyelin. Within the PLB4 genotype there were a range of age-dependent increases in metabolites. This study indicates that gender-specific responses occur in models of AD-like pathology, but importantly, when changes in PLB4 mice (where Aβ oligomers predominate) are compared with APP/PS1 mice (where Aβ plaques predominate) there are consistent and also divergent effects on the brain metabolome.