9 research outputs found

    African and European local ancestry surrounding Apolipoprotein E has a differential biological effect upon acute amyloid beta exposure in iPSC‐differentiated astrocytes

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    Background Studies have shown that the lower risk associated with the ε4 allele for African ancestry is associated with the local ancestry (LA) surrounding the ApoE gene. Previous studies have shown differences between ApoE3 and ApoE4 alleles in isogenic induced pluripotent stem cell (iPSC) models when exposed to Aβ. We hypothesized that ApoE4 individuals with African LA would respond differently to Aβ compared to European ApoE3 and European ApoE4 LA lines. However, as we cannot produce isogenic lines to test LA, we used RNA expression changes to Aβ exposure to increase our sensitivity to potential differences. Method We differentiated European LA ε4/ε4 and African LA ε4/ε4 allele astrocytes from iPSC lines. Astrocytes were exposed to exogenous Aβ and RNA was obtained at 0 and 24 hours. We performed bioinformatic analyses with the STAR algorithm and differential expression calculation using linear models implemented in edgeR. Pathway enrichment analysis for Gene Ontology Biological Processes, KEGG and Reactome pathways was performed using Metascape. Result Twenty‐four hours following Aβ exposure, 524 and 671 genes were deferentially expressed from baseline in African and European LA lines respectively. Analysis of the unregulated genes in the two different ancestries revealed markedly different pathways. The unregulated genes in African LA astrocytes were enriched for Ribosome Biogenesis and RNA modification processes while the upregulated genes in the European LA astrocytes were enriched for Cell Cycle and DNA modification processes. In the European LA astrocytes, downregulated genes were enriched for Synaptic Assembly and Kainate Receptor Activity while in the African LA astrocytes downregulated genes enriched for Extracellular Matrix‐related processes. Conclusion Our initial results suggest that the two ancestries respond differently to Aβ exposure. Whether this is due to global or local ancestry differences is unclear. Further studies including astrocytes bearing African LA ε3/ε3 are needed to clarify that question. Both ribosomal dysfunction and astrocyte‐neuronal and astrocyte‐microglia synaptic assembly have been implicated in Aβ clearance and/or AD. A potential link between LA and the regulation of these processes due to Aβ exposure could pave the path to a better understanding of LOAD pathology
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