Unlike neurons, NF-κB is present in the cytoplasm as an inactive complex with the IκB proteins in glial cells under physiological conditions
In neuronal cells Aβ1-42 peptide has been shown to regulate APP and BACE1 proteins in NF-κB dependent manner
Excessive accumulation of Aβ1-42 stimulates microglial cells by signaling via receptor associated advanced glycation end products (RAGE) and peroxisome proliferator-activated receptor-γ (PPAR-γ), phosphorylates IKK proteins, and enhances NF-κB mediated transactivation of inflammatory cytokines and neurotoxic molecules such as glutamate and reactive oxygen species (ROS)/induced nitric oxide synthase (iNOS) [12] (Fig 2B)
Exposure of primary neuronal cells or post-mitotic neurons to Aβ1-42 peptide has been shown to strongly activate the p50:p65 dimers and mediate neuronal cell death (Fig 1)
Under physiological conditions activation of NF-κB by endogenous Aβ reduces βAPP, BACE1 and the γ-secretase activity, thereby lowering Aβ processing and facilitating Aβ homeostasis
However in AD, exposure to high Aβ concentrations upregulates NF-κB activation increasing βAPP and Aβ processing, precipitating a feed-back loop that favor exacerbated Aβ production
Mechanistically, the Aβ induced neuronal apoptosis has been attributed to the increase in the ratio of proapoptotic gene (BAX) transcription to that of the anti-apoptotic gene Bcl-Xl, and/or to the reduction in constitutively activated NF-κB with consequent increase in the cytoplasmic IκB proteins
This is supported by the observation that in mixed neuronal-glial cell cultures, Aβ induces increasing degree of neurotoxicity in an NF-κB dependent manner in the presence of higher proportion of glial cells
Aβ has been shown to upregulate APOE in astroglial cells. This upregulation was inhibited by decoy-κB nucleotides supporting a critical role for NFκB in APOE function
Glutamate induced stimulation of cerebellar granule cells via the N-methyl-D-aspartate (NMDA) receptor activate p65:p50 dimers and enhance transactivation of pro-apoptotic factors
A consequence of intracellular and parenchymal accumulation of NPs and NFTs is activation of NF-κB in the neural and glial cells with subsequent protective or detrimental effects
Increased presence of activated glial cells presenting elevated NF-κB and HLA-DR expression are commonly observed around the Aβ plaques in postmortem AD tissue
In primary neuronal cells, exposure to Aβ25-35 peptide increase NF-κB mediated transactivation of manganese superoxide dismutase (Mn-SOD), suppress peroxinitrite production and inhibit membrane depolarization, thereby preventing apoptosis induced by oxidative stress
Several kinase pathways including the calcium-calmodium dependent kinase-II (CaMK), the protein kinases-C (PKC) and the ras/phosphatidylinositol 3-kinase (PI3K) pathways have been implicated in activating neuronal NF-κB signaling
A number of physiological stimuli including membrane depolarization or glutamergic signal transduction lead to rapid activation of the inducible NF-κB localized in the synapses, cytoplasm and dendrites of the neurons
In conditional neuronal NF-κB-deficient mice, loss of NF-κB signaling impaired synaptic transmission, spatial memory formation, and plasticity
Complete abrogation of the DNA binding ability of NFκB factors induces apoptosis of the neuronal cells
Cell death is preceded by reduction in the NF-κB regulated transcription of anti-apoptotic genes suggesting that a minimal threshold of NF-κB activity is needed for neuronal survival
Various endogenous and exogenous stimuli activate NF-κB enhancing transactivation of inflammatory molecules and production of free radicals in glial cells
Decoy κB nucleotides mediate cell death by blocking neurotrophins and anti-apoptotic factors supporting an essential role for NF-κB in the neuroprotective process
These NF-κB mediated neuroprotective effects have been largely observed in early stages of neuronal regeneration in AD
Comparison of the cellular distribution of NF-κB in the nucleus basalis of Meynert of AD and control patients showed that the proportion of large cholinergic neurons with elevated nuclear p65 was significantly increased in AD, suggesting an association between NF–κB functions and the process of cholinergic degeneration
These observations substantiate a direct role of neuronal NF–κB activation in the pathogenesis of AD
Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients
Furthermore NF-κB specific inhibitor prevents iNOS and ROS upregulation in Aβ stimulated cultures of astrocytes or mixed cortical cells
Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues
The constitutive form is transcriptionally active as evidenced by the nuclear localization of the p50 and p65 subunits in the neurons of the cortex and hippocampus
In metabotrophic glutamate receptor-5 (mGlu5) agonist pretreated primary cortical neurons or neuroblastoma cells, Aβ induced toxicity was suppressed by selective activation of c-rel containing NF-κB dimers and transactivation of anti-apoptotic genes, Mn-SOD and Bcl-Xl [26] (Figs 1B, 2A)
. Consistent with the cellular studies, increased immunostaining for NF-κB-p65 has been observed in neurons and their processes in the hippocampal formation and entorhinal cortex in AD
Stimulation with the Aβ25-35 fragments induces secretion of cytokines such as TNF-α and of neurotrophic factors such as nerve growth factor (NGF) and brain derived nerve factor (BDNF) in NF-κB-dependent manner
In AD brains, miRNA-125b is observed as the most abundant exhibiting strong positive correlation with glial fibrillary acidic protein and vimentin and negative correlation with reduced cyclin dependent kinase 2A
Stimulation of neuronal cells by TNF-α has been shown to upregulate transactivation of anti-apoptotic gene products and neurotrophins such as Bcl-2 and NGF respectively
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.