[P2–114]: PATIENT‐DERIVED IPSC MODEL OF AN ABCA7 FRAMESHIFT DELETION ASSOCIATED WITH ALZHEIMER's DISEASE IN AFRICAN AMERICANS
Year: 2017
Type: article
Abstract: The ATP-binding cassette, sub-family A (ABC1), member 7 (ABCA7) gene has been implicated as a risk factor in Alzheimer's disease (AD) across populations including African American (AA), Asian, and non-Hispanic white (NHW) populations. However, the risk effect of ABCA7 in AA is significantly stronger than in the Asian and NHW populations. We recently reported a 44 base pair deletion in AA significantly associated with disease (cases=15.2%, controls=9.74%, p=1.414x10, Cukier, et al, 2016). The deleted allele is predicted to produce a frameshift mutation (p. Arg578Alafs) resulting in a truncated protein. To further understand the mechanism by which the ABCA7 deletion may be acting, induced pluripotent stem cells (iPSC) lines were developed from the blood of two unrelated AA AD individuals bearing the deletion, as well as two aged and ethnically matched cognitively normal individuals. Each iPSC line generated was validated for pluripotency through immunocytochemical staining and shown to be negative for any large scale chromosomal abnormalities via karyotyping. The iPSC lines were cultured as embroid bodies, then neural rosettes, and finally as a monolayer to promote cortical neuronal differentiation. RNA from the AD individuals have demonstrated that a stable RNA transcript is being produced from the ABCA7 deletion allele. iPSC-derived cortical neurons were then examined by ELISA to measure levels of pathogenic β40-amyloid at day 45 and 95 of differentiation. While higher levels of β40-amyloid were found in the older neurons compared to younger neurons in both cases and controls, the AD cases had higher levels of β40-amyloid compared to controls. This deletion in ABCA7 may represent an ethnic specific, pathogenic alteration in AD resulting in impaired APP processing and increase production of toxic β-amyloid production.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2766760497