Pluto Bioinformatics

GSE144254: APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain.

Bulk RNA sequencing

The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression and lipids in Alzheimers disease (AD) brain. The results so far have prompted further research using multi-omics approaches. These approaches become particularly relevant, considering the inheritance of APOE4 allele as a major genetic risk factor of AD, disease protective effect of APOE2 allele, and a major role of APOE in brain lipid metabolism. Significantly affected GO terms and pathways were determined based on the comparisons of APOE2/c datasets to those of APOE3/3 and APOE4/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, 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 in APOE2/c brain samples compared to both APOE3/3 and APOE4/c. The analysis of lipidomics datasets revealed significant changes in ten major lipid classes (exclusively a decrease in APOE4/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 the 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 the proteasomal system and autophagycanonical and selective, facilitating intracellular degradation, protein entry into ER, response to ER stress, nucleolar modifications of mRNA, and likely myelination in APOE2/c brains. 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. SOURCE: Iliya Lefterov (iliyal@pitt.edu) - Lefterov/Koldamova University of Pittsburgh