NF-κB in neurodegenerative diseases: Recent evidence from human genetics

Abstract

The transcription factor NF-κB is commonly known to drive inflammation and cancer progression, but is also a crucial regulator of a broad range of cellular processes within the mammalian nervous system. In the present review, we provide an overview on the role of NF-κB in the nervous system particularly including its constitutive activity within cortical and hippocampal regions, neuroprotection as well as learning and memory. Our discussion further emphasizes the increasing role of human genetics in neurodegenerative disorders, namely, germline mutations leading to defects in NF-κB-signaling. In particular, we propose that loss of function mutations upstream of NF-κB such as ADAM17, SHARPIN, HOIL, or OTULIN affect NF-κB-activity in Alzheimer’s disease (AD) patients, in turn driving anatomical defects such as shrinkage of entorhinal cortex and the limbic system in early AD. Similarly, E3 type ubiquitin ligase PARKIN is positively involved in NF-κB signaling. PARKIN loss of function mutations are most frequently observed in Parkinson’s disease patients. In contrast to AD, relying on germline mutations of week alleles and a disease development over decades, somatic mutations affecting NF-κB activation are commonly observed in cells derived from glioblastoma multiforme (GBM), the most common malignant primary brain tumor. Here, our present review particularly sheds light on the mutual exclusion of either the deletion of NFKBIA or amplification of epidermal growth factor receptor (EGFR) in GBM, both resulting in constitutive NF-κB-activity driving tumorigenesis. We also discuss emerging roles of long non-coding RNAs such as HOTAIR in suppressing phosphorylation of IκBα in the context of GBM. In summary, the recent progress in the genetic analysis of patients, particularly those suffering from AD, harbors the potential to open up new vistas for research and therapy based on TNFα/NF-κB pathway and neuroprotection.

Identification of the pathogenic relationship between Long COVID and Alzheimer's disease by bioinformatics methods

“…Glial brillary acidic protein (GFAP), a marker of reactive astrogliosis, is increased in the blood of AD patients [30] . In addition, the NFKBIA gene is also indirectly associated with AD, and its polymorphism is associated with susceptibility to autoimmune diseases and in ammatory diseases [31] . It is generally noted that in ammation, as a research hots pot of AD, has maintained a very mysterious mechanism.…”

Neuroinflammation, Oxidative Stress, Apoptosis, Microgliosis and Astrogliosis in the Cerebellum of Mice Chronically Exposed to Waterpipe Smoke

“…In an attempt to investigate the underlying mechanism of the increase in oxidative stress and neuroinflammation observed in the present work, we measured the transcription factor NF-κB. The latter is commonly known as a critical regulator of both oxidative stress and inflammatory responses through the regulation of oxidative stress and numerous proinflammatory genes such as cytokines [ 65 , 66 , 67 ]. Our data show that WPS induced a significant increase in the levels of NF-κB.…”

IKK/NF‐κB and ROS signal axes are involved in Tenacissoside H mediated inhibitory effects on LPS‐induced inflammatory osteolysis

“…This process, in turn, causes IκB proteins to be rapidly ubiquitinated and degraded via the ubiquitin‐mediated proteasomal degradation pathway. Upon the degradation of IκB, NF‐κB proteins can move from the cytoplasm to the nucleus and bind to their respective DNA binding sites, where they regulate the transcription of a diverse collection of downstream target genes 33,34 . It has been shown that TDH is beneficial in treating a diverse range of disorders via mediating NF‐κB signalling pathway in various cell types 22,35 .…”