Pluripotent Cells Expressing APOE4 Exhibit a Pronounced Pro-Apoptotic Phenotype Accompanied by Markers of Hyperinflammation and a Blunted NF-κB Response.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

NF-kappa B*/metabolism ; Apolipoprotein E4*/metabolism ; Apolipoprotein E4*/genetics ; Apoptosis*/genetics ; Inflammation*/metabolism ; Inflammation*/genetics ; Inflammation*/pathology ; Induced Pluripotent Stem Cells*/metabolism; Biomarkers/metabolism ; Octamer Transcription Factor-3/metabolism ; Octamer Transcription Factor-3/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Chemokine CXCL10/metabolism ; Chemokine CXCL10/genetics ; Cyclooxygenase 2/metabolism ; Cyclooxygenase 2/genetics ; Chemokine CCL2/metabolism ; Chemokine CCL2/genetics ; Apolipoprotein E3/metabolism ; Apolipoprotein E3/genetics ; Tumor Necrosis Factor-alpha/metabolism ; Humans ; Signal Transduction ; Phenotype ; Cell Line

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses an increasing burden on society. It is characterized by the presence of neurofibrillary tangles (NFTs) and amyloid-beta (Aβ) plaques. AD is a multifactorial disease, with one of the strongest genetic risk factors being the APOE4 allele. In this study, we investigated the impact of APOE4 on NF-κB signaling in induced pluripotent stem (iPS) cells. Our results indicate that APOE4 may influence the subcellular localization of the pluripotency marker OCT4, showing a predominantly nuclear localization in APOE4 cells, whereas it appears cytoplasmic in APOE3 cells. Additionally, NF-κB activation via its canonical subunits is blunted in APOE4 cells. Interestingly, APOE4 cells still exhibit increased transcription of key hyperinflammatory markers CCL2, CXCL10 and COX2, which are known NF-κB target genes, and exhibit a significantly higher rate of apoptosis compared to APOE3 cells-independent of TNF-α stimulation. Moreover, an elevated incidence of DNA double-strand breaks was observed in APOE4 cells. However, the precise molecular mechanisms by which APOE4 suppresses NF-κB activation while simultaneously promoting inflammation and apoptosis remain unclear. Further research is required to elucidate these underlying pathways.

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Keywords: APOE; Alzheimer’s disease; DNA damage; NF-κB; TNF-α; apoptosis; double strand breaks; hyperinflammation; iPSC; necroptosis

0 (NF-kappa B)
0 (Apolipoprotein E4)
0 (Biomarkers)
0 (Octamer Transcription Factor-3)
0 (Chemokine CXCL10)
EC 1.14.99.1 (Cyclooxygenase 2)
0 (Chemokine CCL2)
0 (POU5F1 protein, human)
0 (Apolipoprotein E3)
0 (Tumor Necrosis Factor-alpha)

Date Created: 20251016 Date Completed: 20251016 Latest Revision: 20251019

20260130

PMC12524803

10.3390/ijms26199283

41096552