P4-182: Inhibition of ABCG2 transport function by amyloid-beta peptide augments cellular oxidative stress and inflammatory gene expression in cells

Alzheimer’s disease (AD) is tightly linked to oxidative stress since amyloid beta-peptide (Aβ) aggregates generate free radicals. Moreover, the aggregation of Aβ is increased by oxidative stress, and the neurotoxicity induced by the oligomers and fibrils is in part mediated by free radicals. Interestingly, it has been reported that oxidative stress can also induce BACE1 transcription and expression. BACE1 is the key enzyme in the cleavage of the amyloid precursor protein to produce Aβ, and the expression of this enzyme has been previously shown to be enhanced in the brains of Alzheimer’s patients. Here, we have found that BACE1 expression is increased in the hippocampi from AD patients at both the early (Braak stage II) and late (Braak stage VI) stages of the disease as studied by immunohistochemistry and western blot. To address the role of Aβ and oxidative stress in the regulation of BACE1 expression, we have analyzed the effect of subtoxic concentrations of Aβ oligomers (0.25 μM) and H2O2 (10 mM) on a human neuroblastoma cell line. Firstly, our results show that Aβ oligomers and H2O2 induce an increase of BACE1 mRNA as we studied by qPCR. Regarding BACE1 translation, it is dependent on the phosphorylation of the eukaryotic initiation factor 2α (eIF2α), since BACE1 mRNA bears a 5′UTR that avoids its translation under basal conditions. BACE1 5′UTR contains four upstream initiating codons (uAUGs), and its translation is activated when eIF2α is phosphorylated. Consistently, we have obtained that Aβ oligomers and H2O2 increase the levels of BACE1 and p-eIF2α assayed by western blot and confocal microscopy. Our results suggest that Aβ oligomers increase BACE1 translation by phosphorylating eIF2α in a process that involves oxidative stress and conforms a pathophysiological loop, where the Aβ once aggregated favors its own production continuously by the increase in BACE1 expression as observed in AD patients.

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Enhanced vulnerability to oxidative stress and induction of inflammatory gene expression in 3‐phosphoglycerate dehydrogenase‐deficient fibroblasts

FEBS Open Bio ◽

10.1002/2211-5463.12429 ◽

2018 ◽

Vol 8 (6) ◽

pp. 914-922 ◽

Cited By ~ 2

Author(s):

Momoko Hamano ◽

Yurina Haraguchi ◽

Tomoko Sayano ◽

Chong Zyao ◽

Yashiho Arimoto ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Inflammatory Gene Expression ◽

Inflammatory Gene ◽

Phosphoglycerate Dehydrogenase

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Oxidative stress and macrophage function: a failure to resolve the inflammatory response

Biochemical Society Transactions ◽

10.1042/bst0350284 ◽

2007 ◽

Vol 35 (2) ◽

pp. 284-287 ◽

Cited By ~ 54

Author(s):

P. Kirkham

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Inflammatory Response ◽

Carbonyl Stress ◽

Apoptotic Cells ◽

Inflammatory Gene Expression ◽

Macrophage Function ◽

Inflammatory Gene ◽

Ecm Proteins ◽

Inflammatory State

The suppression of pro-inflammatory gene expression along with the clearance of apoptotic cells by phagocytosis can play an important role in resolving the inflammatory response. Any impairment of these processes can therefore lead to a chronic inflammatory state. Oxidative stress can have both direct and indirect effects on macrophage function. This mini-review highlights a mechanism through which oxidative stress via the production of reactive carbonyls alters the ECM (extracellular matrix) environment of macrophages, thereby altering their behaviour. Carbonyl modification of ECM proteins causes increased macrophage adhesion and activation through receptors that are also involved in phagocytosis. Moreover, interaction of macrophages with these carbonyl-modified ECM proteins leads to decreased phagocytic activity towards apoptotic cells. At a more direct level, both oxidative and carbonyl stress inhibits activity of the transcriptional co-repressor HDAC-2 (histone deacetylase 2), which under normoxic conditions helps to suppress pro-inflammatory gene expression. Consequently, macrophages activated under conditions of oxidative or carbonyl stress can lead to a more enhanced inflammatory response. Coupled with an impairment of the phagocytic response, this can lead to ineffective clearance of apoptotic cells and secondary necrosis, with the result being failure to resolve the inflammatory response and the establishment of a chronic inflammatory state.

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