APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain

Abstract

AbstractBackgroundThe 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 ofAPOEε4allele as a major genetic risk factor of AD, disease protective effect ofAPOEε2allele, and a major role of APOE in brain lipid metabolism.MethodsPostmortem brain samples from inferior parietal lobule genotyped asAPOEε2/c(APOEε2/carriers),APOEε3/3, andAPOEε4/c (APOEε4/carriers), age- and gender-matched, were used to revealAPOEallele-associated changes in transcriptomes and lipidomes. Differential gene expression and co-expression network analyses were applied to identify up- and downregulated Gene Ontology (GO) terms and pathways for correlation to lipidomics data.ResultsSignificantly affected GO terms and pathways were determined based on the comparisons ofAPOEε2/cdatasets to those ofAPOEε3/3andAPOEε4/cbrain 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, and response to unfolded protein, as well as mitochondrial function, electron transport, and ATP synthesis. Small nucleolar RNA coding units important for posttranscriptional modification of mRNA and therefore translation and protein synthesis were upregulated inAPOEε2/cbrain samples compared to bothAPOEε3/3andAPOEε4/c. The analysis of lipidomics datasets revealed significant changes in ten major lipid classes (exclusively a decrease inAPOEε4/csamples), most notably non-bilayer-forming phosphatidylethanolamine and phosphatidic acid, as well as mitochondrial membrane-forming lipids.ConclusionsThe results of this study, despite the advanced stage of AD, point to the significant differences in postmortem brain transcriptomes and lipidomes, suggestingAPOEallele associated differences in pathogenic mechanisms. Correlations within and between lipidomes and transcriptomes indicate coordinated effects of changes in the proteasomal system and autophagy—canonical and selective, facilitating intracellular degradation, protein entry into ER, response to ER stress, nucleolar modifications of mRNA, and likely myelination inAPOEε2/cbrains. Additional research and a better knowledge of the molecular mechanisms of proteostasis in the early stages of AD are required to develop more effective diagnostic approaches and eventually efficient therapeutic strategies.