Frontiers Journal of Neurology & Neuroscience

Apoe2 Driven Differences In Transcriptomic And Lipidomic Profiles Of AD Brain

Abstract

The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression and lipids in Alzheimer’s disease (AD) brain. The results so far have prompted further research using "multi-omics" approaches. These approaches become particularly relevant, considering the inheritance of APOE?4 allele as a major genetic risk factor of AD, disease protective effect of APOE?2 allele, and a major role of APOE in brain lipid metabolism. Postmortem brain samples from inferior parietal lobule genotyped as APOE?2/c (APOE?2/carriers), APOE?3/3 and APOE?4/c (APOE?4/carriers), age and gender matched were used to reveal APOE allele associated changes in transcriptomes and lipidomes. Differential gene expression and co-expression network analyses were applied to identify up- and down-regulated Gene Ontology (GO) terms and pathways for correlation to lipidomics data.

Significantly affected GO terms and pathways were determined based on the comparisons of APOE?2/c datasets to those of APOE?3/3 and APOE?4/c brain samples. The analysis of lists of genes in highly correlated network modules and of those differentially expressed, demonstrated significant enrichment in GO terms associated with genes involved in intracellular proteasomal and lysosomal degradation of proteins, protein aggregates and organelles, ER stress, response to unfolded protein, as well as mitochondrial function, electron transport and ATP synthesis. The analysis of lipidomics datasets revealed significant changes in 10 major lipid classes (exclusively a decrease in APOE?4/c samples), most notably non-bilayer forming phosphatidylethanolamine and phosphatidic acid, as well as mitochondrial membrane forming lipids.

The results of this study, despite the advanced stage of AD, point to significant differences in postmortem brain transcriptomes and lipidomes, suggesting APOE allele associated differences in pathogenic mechanisms. Correlations within and between lipidomes and transcriptomes indicate coordinated effects of changes in proteasomal system and autophagy – canonical and selective, facilitating intracellular degradation, protein entry into ER and response to ER stress in APOE?2/c brains.

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