Graduate and Postdoctoral Research Symposium 2020 has ended
avatar for Oded Oron

Oded Oron

Molecular Characterization of the Impact Local Ancestry has on ApoE Functionality
Poster Presenter #16
Postdoctoral Associate in Neuroscience
Apolipoprotein E (APOE) polymorphisms are the strongest predictors of Late Onset Alzheimer’s Disease (LOAD) development. The ApoE ε4 allele confers the highest risk compared to the ε3 and ε2 alleles. Interestingly, people of African descent harboring the ε4 allele are significantly less likely to develop LOAD compared to people of European descent harboring ApoE ε4. Previous work performed in our group analyzing the admixture genomes of patients having both African and European ancestry, suggests that a 2 megabase Local ancestry Block (LaB) surrounding of APOE gene may hold the key to the lower disease risk found in African populations harboring the ε4 genotype.
A great challenge in studying large LaBs and their role, is producing an in-vitro model that can be tested molecularly and functionally. In this study, we produced iPSC lines derived from patients harboring a European LaB with either a ε3/3 or ε4/4 alleles, and African LaB with the ε4/4 allele. From these iPSC lines we generated astrocytes – a cell type highly relevant to Alzheimer disease – to facilitate molecular and functional characterization.
First, we investigated differences in APOE expression, and cholesterol and amyloid β metabolism as those are abnormal in patients who develop LOAD. In our preliminary data, we show that APOE is upregulated in cells harboring an African LaB compared to the cells harboring the European LaB. Additionally, cholesterol production is increased in cells harboring a European LaB with the ε4/4 allele compared to cells harboring a European LaB with the ε3/3 allele. In the amyloid β uptake test, the European ε3/3 cells took up more amyloid β compared to the other cell lines.
Although preliminary, these results suggest unique role for the African LaB in regulating APOE expression, and that cholesterol and Amyloid β metabolism are driven by a more complex mechanism. In addition, we will perform transcriptome analysis to give us additional insight into the molecular pathways responsible for driving these ethnic–specific differences in AD risk.

Additional author(s): Krisna Maddy, Holly Cukier, Margaret Pericak-Vance, Jeffery Vance, Derek Dykxhoorn