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- W2895872000 abstract "The application of advanced sequencing technologies and improved mass-spectrometry platforms have revealed significant changes in gene expression and lipids in brain of AD patients. The results prompted further research using “multi-omics” approaches. These approaches become particularly relevant considering the inheritance of APOEε4 allele as a major genetic risk factor of AD, and aggravated AD phenotype in APOEε4/4 patients. Postmortem brain samples from inferior parietal lobule of APOEε2/3 APOEε3/3, APOEε4/4 and APOEε3/4 AD patients at advance stage of the disease were used to determine APOE allele associated changes. Differential gene expression was analyzed using Empirical Bayes strategy and quantile-adjusted conditional maximum likelihood. Shotgun Lipidomics assays were applied to determine the association of APOE allele combinations with brain lipidomes. MixOmics algorithm was used to correlate trends and changes in the transcriptomics and lipidomics datasets. The inflammation and immune response were among the most significantly affected categories in APOEε4/4 transcriptome encompassing homeostatic and disease associated microglia-specific genes. Among the homeostatic microglia-specific genes increased in APOEε4/4 samples were TMEM119, ITGAM/CD11B, TGFB1 and PLD4, and among the disease-associated - APOE, AXL, cathepsins, chemokines, TSPO and CLEC5A. Changes in expression level of genes coding for structural units of mitochondrial permeability transition pore, and of genes involved in initial, critical steps of autophagy were identified as an important aspect of APOEε4/4 transcriptomic profile and are reported for the first time. The analysis of lipidomics datasets revealed a pronounced decrease of cardiolipin and phosphatidylethanolamine molecular species in APOEε4/4 brain lipidome. Correlation analyses within and between lipidomes and transcriptomes also indicate that the availability of lipids and their APOE mediated transport are possibly important for differences between APOEε4/4, APOEε3/3 and APOEε3/4 phenotypes. Despite the advanced stage of AD there are significant differences in postmortem brain transcriptomes and lipidomes which indicate APOE associated differences in pathogenic mechanisms. The significant difference between APOEε4/4 and APOEε3/4 transcriptomes compared to the difference between APOEε3/3 and APOEε3/4 demonstrated here, suggests that APOEε4/4 and APOEε3/4 transcriptomics datasets should be evaluated separately, which warrants a careful consideration in selecting groups of AD patients for comparison." @default.
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- W2895872000 date "2018-07-01" @default.
- W2895872000 modified "2023-10-16" @default.
- W2895872000 title "P4‐253: MULTI‐OMICS PROFILING IDENTIFIES APOE‐ALLELE‐ASSOCIATED LIPID AND GENE EXPRESSION PATTERNS IN ALZHEIMER'S DISEASE" @default.
- W2895872000 doi "https://doi.org/10.1016/j.jalz.2018.07.075" @default.
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