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

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 <i>APOE4</i> 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 <i>APOE4</i> cells, whereas it appears cytoplasmic in <i>APOE3</i> cells. Additionally, NF-κB activation via its canonical subunits is blunted in <i>APOE4</i> cells. Interestingly, <i>APOE4</i> cells still exhibit increased transcription of key hyperinflammatory markers <i>CCL2</i>, <i>CXCL10</i> and <i>COX2</i>, which are known NF-κB target genes, and exhibit a significantly higher rate of apoptosis compared to <i>APOE3</i> cells-independent of TNF-α stimulation. Moreover, an elevated incidence of DNA double-strand breaks was observed in <i>APOE4</i> 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.