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

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Alzheimer's disease (AD) involves complex genetic and metabolic changes.
• The apolipoprotein E (APOE) gene, particularly APOEε4 and APOEε2 alleles, significantly influences AD risk and brain lipid metabolism.
• Multi-omics approaches are crucial for understanding these intricate relationships.

Purpose of the Study:

• To investigate APOE allele-associated differences in gene expression and lipid profiles in postmortem human brain samples.
• To correlate transcriptomic and lipidomic data to elucidate molecular mechanisms in Alzheimer's disease.

Main Methods:

• Analysis of postmortem inferior parietal lobule brain samples from individuals genotyped for APOEε2, APOEε3, and APOEε4 alleles.
• Application of differential gene expression, co-expression network analysis, and lipidomics.
• Identification of Gene Ontology (GO) terms and pathways correlated with lipidomics data.

Main Results:

• Significant alterations in GO terms related to proteasomal and lysosomal degradation, ER stress, and mitochondrial function were observed.
• APOEε2 carriers showed upregulated small nucleolar RNA coding units, impacting mRNA modification and protein synthesis.
• Lipidomics revealed significant changes in ten major lipid classes, with notable decreases in phosphatidylethanolamine and phosphatidic acid in APOEε4 carriers.

Conclusions:

• APOE alleles are associated with distinct pathogenic mechanisms in Alzheimer's disease, evident in transcriptomic and lipidomic profiles.
• Correlations suggest coordinated effects on proteostasis, ER stress response, and myelination, particularly in APOEε2 brains.
• Further research into proteostasis mechanisms in early AD stages is needed for improved diagnostics and therapeutics.