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iPSC‐derived neurons and microglia with an African‐specific ABCA7 frameshift deletion have impaired function
Author(s) -
Cukier Holly N.,
LaverdePaz Juliana,
Ramirez Juliana,
Adams Larry D.,
Starks Takiyah D.,
Vance Jeffery M.,
Cuccaro Michael L.,
BlurtonJones Mathew,
Haines Jonathan L.,
Byrd Goldie S.,
PericakVance Margaret A,
Dykxhoorn Derek M.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.046109
Subject(s) - frameshift mutation , microglia , biology , induced pluripotent stem cell , allele , mutation , genetics , gene , immunology , embryonic stem cell , inflammation
Background 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. However, the risk effect of ABCA7 in African Americans (AAs) is stronger than in non‐Hispanic white (NHW) populations. We identified a 44 base pair deletion in AA significantly associated with disease (cases = 15.2%, controls = 9.74%, p = 1.414 × 10 −5 , Cukier, et al, 2016). The deleted allele is predicted to produce a frameshift mutation (p.Arg578Alafs), resulting in a truncated protein that may interfere with its normal functions, including APP processing and Aβ clearance. Method 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 heterozygous for the deletion, as well as age matched cognitively normal individuals. The iPSC lines were differentiated into cortical neurons and microglia, as both cell types endogenously express ABCA7 . Result Each iPSC line generated was karyotyped and validated for pluripotency through immunocytochemical staining. RNA from the cases demonstrated that a stable RNA transcript is produced from the ABCA7 deletion allele. Preliminary results from iPSC‐derived neurons and microglia identified impaired functions in both cells types. Cortical neurons from patients produced higher levels of Aβ40 and Aβ42 compared to controls. In addition, while the patient‐derived microglia had normal rates of phagocytosis, they were impaired in the uptake and clearance of fibrillar Ab. Furthermore, when exposed to the proinflammatory stimulus lipopolysaccharide (LPS), the patient‐derived microglia had decreased cytokine responses. Conclusion This deletion in ABCA7 is an ethnic specific, pathogenic alteration in AD that may result in an increased production of toxic β‐amyloid production in neurons and a depressed ability to clear Ab and impaired responsiveness to proinflammatory signals in microglia.