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 Alzheimer's 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 brain's 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 Alzheimer's disease risk allele E4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer's disease and illustrate the utility of both zebrafish and knock-in, single EOfAD mutation models for understanding the causes of this disease.

In-Frame and Frameshift Mutations in Zebrafish Presenilin 2 Affect Different Cellular Functions in Young Adult Brains

“…In conclusion, our results support that frameshift and in-frame mutations in the presenilins have distinct effects on the brain transcriptome, consistent with the reading frame preservation rule of presenilin EOfAD-causative mutations. The data presented here, along with our growing collection of BeST analyses (summarized in [ 56 ]), indicates that changes to mitochondrial and ribosomal functions are effects-in-common of heterozygosity for EOfAD-like mutations in different genes. These may be early cellular stresses which eventually lead to AD pathology, and warrant investigation for discovery of therapeutic targets.…”