P3‐206: Investigating Ancestry Specific Differences in Apoe Function Using Induced Pluripotent Stem Cells
Year: 2019
Type: article
Abstract: The Apoliproprotein E (APOE) e4 allele is the most significant genetic risk factor for late-onset Alzheimer disease (AD). However, the risk associated with the APOE e4 allele differs across populations. For example, in individuals of African ancestry, the APOE e4 allele confers a lower risk for AD than the same allele in individuals of European or Asian ancestry. Recent genetic analyses suggest that there are additional, population-specific genetic variants in the region surrounding the APOE gene that influence AD risk (Rajabli, et al, 2018). However, how these population-specific effects impact AD pathogenesis remains an open question. To begin to understand the population-specific effects of the APOE genomic region, genomic screening was performed to identify individuals with either the African or European APOE local ancestry. Induced pluripotent stem cells (iPSC) bearing the APOE e4/e4 and e3/e3 alleles with either local ancestries of African or European background were derived. These iPSC lines were differentiated into astrocytes and neurons to be functionally characterized using transcriptomic, biochemical, and cell biological approaches. iPSC lines were derived from individuals bearing the African or European local ancestry around the APOE gene as defined as the region covered by chr19: 44,000,000–46,000,000. These iPSC lines were each validated for pluripotency by immunocytochemistry for the following pluripotency and stem cell markers – SOX2, OCT3/4, Nanog, KLF4, TRA-1-60, and TRA-1-81. In addition, these lines were analyzed for genomic stability by G-band karyotyping. No differences in the ability to differentiate into neurons or astrocytes were observed between the APOE e4/e4 and APOE e3/e3 lines. However, APOE e4/e4 iPSC-derived astrocytes showed a reduction in APOE expression over the course of differentiation compared to APOE e3/e3 astrocytes. These studies will be complemented with analyses of the expression and process of the amyloid precursor protein into pathogenic forms of amyloid beta (Ab). The genomic region around the APOE gene influences the risk of APOE e4/e4 in different ancestral populations. Having generated iPSC lines bearing the APOE e4/e4 allele from different populations, they will be used to determine the molecular and cellular mechanisms that underlie these ethnic specific differences.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980726310