Alzheimer’s disease (AD) is a devasting neurodegenerative disease afflicting mainly glutamatergic neurons together with a massive neuroinflammation mediated by the transcription factor NF-κB. A 65%-plus increase in Alzheimer’s patients by 2050 might be a major threat to society. Hallmarks of AD are neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and amyloid beta (Aβ) plaques. Here, we review the potential involvement of transcription factor NF-κB by hereditary mutations of the tumor necrosis factor pathway in AD patients. One of the greatest genetic risk factors is APOE4. Recently, it was shown that the APOE4 allele functions as a null allele in human astrocytes not repressing NF-κB anymore. Moreover, NF-κB seems to be involved in the repair of DNA double-strand breaks during healthy learning and memory, a function blunted in AD. NF-κB could be a friend to healthy neurons by repressing apoptosis and necroptosis. But a loss of neuronal NF-κB and activation of glial NF-κB in AD makes it a foe of neuronal survival. Hopeful therapies include TNFR2 receptor bodies relieving the activation of glial NF-κB by TNFα.

Glioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence. GSCs have thus come into the focus of therapeutic strategies, although their targeting remains challenging. In the present study, we took advantage of three GSCs-populations recently established in our lab to investigate key signaling pathways and subsequent therapeutic strategies targeting GSCs. We observed that NF-κB, a crucial transcription factor in GBM progression, was expressed in all CD44⁺/CD133⁺/Nestin⁺-GSC-populations. Exposure to TNFα led to activation of NF-κB-RELA and/or NF-κB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYC^high GSCs being predominantly located in the tumor spheres (“GROW”-state) while NF-κB-RELA^high GSCs were migrating out of the sphere (“GO”-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-κB using PTDC/Bortezomib or inhibition of MYC by KJ-Pyr-9, which significantly reduced GSC-viability, even in comparison to the standard chemotherapeutic drug temozolomide. As an additional cell-therapeutic strategy, we showed that NK cells could kill GSCs. Our findings offer new perspectives for developing efficient patient-specific chemo- and immunotherapy against GBM.

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.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by progressive memory impairment and cognitive decline. The APOE4 allele represents one of the most prominent genetic risk factors. In this study, we investigated the impact of APOE4 on the cholinergic neuronal development and on the neuronal inflammatory response to TNF-α stimulation. To address this, human induced pluripotent stem cells (hiPSCs) carrying a homozygous APOE4 genotype and an isogenic APOE3 control were differentiated into cholinergic-like induced neurons (iNs) by LHX8 overexpression. APOE4 was associated with accelerated early neuronal differentiation, as reflected by earlier downregulation of the progenitor marker Nestin. However, delayed expression of synaptophysin indicated impaired synaptic maturation. Functionally, APOE3 iNs exhibited a robust but temporally regulated response to TNF-α, whereas APOE4 iNs were characterized by a delayed yet sustained induction of inflammatory signaling. Moreover, APOE4 iNs displayed an enhanced stress-associated transcriptional response at early differentiation stages. Collectively, these findings suggest that APOE4 influences both neuronal development and the timing and persistence of inflammatory responses, potentially predisposing cholinergic neurons to later dysfunction in AD.

The APOE4 allele represents the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet its influence on early cellular programs remains poorly understood. In this study, we investigated transcriptional differences between human induced pluripotent stem cells (iPSCs) carrying the APOE3 or APOE4 genotype. RNA sequencing revealed pronounced genotype-dependent transcriptional changes, with enrichment of genes associated with neural development and metallothioneins in APOE4 cells, while genes related to extracellular matrix organization and cell adhesion were downregulated. Protein–protein interaction network analysis confirmed the presence of clusters linked to neurodevelopmental processes and cellular stress responses in APOE4 cells. Increased expression and nuclear localization of the early neural marker SOX1 further suggest a shift towards early neural lineage commitment in APOE4 cells. In addition, altered expression of early growth response (EGR) transcription factors and reduced TNFR2 protein levels indicated genotype-specific differences in stress and inflammatory signaling pathways. Together, these findings suggest that APOE genotype-dependent alterations in transcriptional regulation, stress responses, and inflammatory signaling may already emerge in pluripotent cells and potentially influence early differentiation programs.