Transcription factor NF-κB: friend or foe of neurons?

Abstract

It is now well established that a number of neurological disorders such as Parkinson's disease and Alzheimer's disease are characterized by the formation of reactive oxygen species (ROS). When produced in excess, ROS can induce oxidative damage to cellular macromolecules and ultimately cell death. Cells employ a number of defense systems against oxidative damage, including antioxidants and antioxidant enzymes. In an effort to develop a better understanding of the molecular mechanisms of the cellular response to a challenge by ROS as observed under certain neuropathological conditions, recent studies have focused on the regulation of gene expression by neurotoxins, including oxidative stressors. One transcription factor that can be activated by oxidative stress is the nuclear transcription factor-kappa B (NF-B). Initially, this factor has been shown to play a major role in the activation of defensive genes during immune and inflammatory responses. But as evidence accumulates suggesting a close association of NF-B activation also with the neuropathology occurring in neurodegenerative processes and neuronal cell death, the search is on to define potential roles for this transcription factor that are specific for neurons. The present article summarizes some of the recent studies that are trying to clarify NF-B's role during neuronal degeneration.

HIF‐1α cytoplasmic accumulation is associated with cell death in old rat cerebral cortex exposed to intermittent hypoxia

“…In hypoxic young cortex, we have demonstrated increased expression and HIF-1α translocation to the nucleus, generally considered as evidence of protein activation, along with no modification of Bcl-2 level, a slight increase in Bax and decrease in IAP-1 levels, all of which might contribute to the observed small number of apoptotic events (Yang & Korskmeyer, 1996). IKB-α expression is thought to act as an important signal in neurodegenerative diseases (Leroualc'h & Behl, 1998), leading to neuron and glial cell apoptosis through hydrogen peroxide formation (Vollgraf et al, 1999). IkB-α phosphorylation and the lack of modification in IAP-1 levels that we have shown in the old cortex exposed to hypoxia may therefore be considered as an attempt by the aged cerebral cortex to counteract oxidative damage by eliminating dead cells (Korhonenet et al, 1997).…”

Amyloid β-protein toxicity and oxidative stress in Alzheimer's disease

“…Based on this structure, several different steroids have been postulated as having potential antioxidant properties (Mooradian 1993). The glucocorticoid receptor and progesterone receptor antagonist RU486 (mifepristone), which can prevent oxidation of the low-density lipoprotein associated with atherosclerosis (Parthasarathy et al 1994) can also act as an antioxidant in neuroprotection (Behl et al 1997a). In studies with Ab, H 2 O 2 and the excitotoxin glutamate, which has also been shown to induce free radicals in susceptible hydrogen peroxide as the mediator of Ab toxicity and as an inducer of a stress response.…”

“…But H 2 O 2 can not only be a source for the generation of hydroxyl radicals, it can also function as an inducer of the activity of the transcription factor NF-kB, which has been shown to activate a stress response in immune cells (Schreck et al 1991). The potential involvement of NF-kB in neurological disorders has been postulated (for reviews, see Kaltschmidt et al 1993;Lezoualch and Behl 1997a). The activity of this transcription factor is also increased by Ab (Behl et al 1994b) and by other fibril-forming peptides (Lezoualch and Behl 1997b), another feature that amyloidogenic peptides share (Fig.…”

Sp1 and Sp3 Are Oxidative Stress-Inducible, Antideath Transcription Factors in Cortical Neurons

“…Finally, we demonstrate that oxidative stress can enhance the activity of an Sp1-dependent reporter gene (data not shown). These results establish Sp1 and Sp3 as redox-regulated transcription factors in embryonic cortical neurons and add these factors to a small list of transcriptional activators and repressors (e.g., nuclear factor B, activator protein-1, and heat shock transcription factor-1) known to be induced by oxidative stress in neurons (Lezoualc'h and Behl, 1998;Post et al, 1998;Bijur et al, 1999;Scortegagna et al, 1999).…”

“…Although it has been established that eukaryotic cells, including neurons, also use transcription factors to respond to ROS and activate protective responses (Lezoualc'h and Behl, 1998;Post et al, 1998;Bijur et al, 1999;Scortegagna et al, 1999), our understanding of the nature of these proteins and their modes of activation in neurons is limited. Primary cultures of cortical neurons provide a convenient in vitro preparation for examining transcription factors that are induced by oxidative stress (Murphy et al, 1989(Murphy et al, , 1990.…”