Comparative analysis of Alzheimer's disease knock-in model brain transcriptomes implies changes to energy metabolism as a causative pathogenic stress

Abstract

Energy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains. Here, we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early-onset familial Alzheimers disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brains energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models of APOE alleles and found the same effect for the late onset Alzheimers disease risk allele {varepsilon}4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimers disease and illustrate the utility of both zebrafish and knock-in, single EOfAD mutation models for understanding the causes of this disease.