ABCG2 reduces ROS‐mediated toxicity and inflammation: a potential role in Alzheimer’s disease

Abstract

J. Neurochem. (2010) 114, 1590–1604. Abstract Alzheimer’s disease is characterized by accumulation and deposition of Aβ peptides in the brain. Aβ deposition generates reactive‐oxygen species (ROS), which are involved in Alzheimer’s inflammatory and neurodegenerative pathology. We have previously observed that, in Alzheimer’s disease brain, ABCG2 is up‐regulated and AP‐1 is activated, but NF‐κB is not activated. In the present study, we examine the roles and mechanism of ABCG2 on ROS generation, inflammatory gene expression and signaling, heme homeostasis and Aβ production in cell models and on inflammatory signaling and Aβ deposition in Abcg2‐knockout and wild‐type mice. Our results show that ABCG2 plays a protective role against oxidative stress by decreasing ROS generation, enhancing antioxidant capacity, regulating heme level, and inhibiting inflammatory response in cell models. ABCG2 inhibits NF‐κB activation but has less effect on AP‐1 activation induced by ROS. This results in inhibition of interleukin‐8 and growth‐related oncogene (GRO) expression induced by ROS via NF‐κB pathway. Abcg2 deficiency increased Aβ deposition and NF‐κB activation in the brains of Abcg2‐knockout mice compared with controls. These findings suggest that ABCG2 may relieve oxidative stress and inflammatory response via inhibiting NF‐κB signaling pathway in cell models and brain tissues and thus may play a potential protective role in Alzheimer’s neuroinflammatory response.

Role of ABC Transporters in the Pathogenesis of Alzheimer’s Disease

“…This result was further confirmed in vitro in N2a-695 cells where overexpression of ABCG2 significantly decreased the processing rate of APP and Aβ production as compared with controls. 126 Lack of difference in ABCG2 expression in the brain vasculature of AD compared to normal cases has also been reported. 59 While further studies are necessary to confirm these results, this discrepancy could be related to regional variations, for example, hippocampal 59 vs occipital cortical 124 regions, in the extent of ABCG2 vascular changes in AD.…”

The Involvement of Cholesterol in Sepsis and Tolerance to Lipopolysaccharide Highlighted by the Transcriptome Analysis of Zebrafish (Danio rerio)

“…Although the role of this protein in zebrafish is still unknown, S100 proteins are endogenous activators of innate immune responses in mammals, and some of them have proinflammatory properties and are associated with different inflammatory diseases, such as inflammatory bowel disease. [82][83][84] Several genes involved in the relief of oxidative stress as a compensatory mechanism were up-modulated in tolerized zebrafish as described for mammals 85,86 ; these include glutathione peroxidase 7 (GPX7), which mitigates the organ dysfunction during chronic inflammation, and phosphoenolpyruvate synthase, which is an essential enzyme when pyruvate and lactate are used as a carbon source. The upmodulation in tolerized fish suggests a mechanism for avoiding the excess of lactate and hypoxia that induces the organ failure associated with sepsis.…”

The ATP-Binding Cassette Transporter ABCG2 Protects Against Pressure Overload–Induced Cardiac Hypertrophy and Heart Failure by Promoting Angiogenesis and Antioxidant Response

“…In fact, it was reported that ABCG2 may relieve oxidative stress and inflammatory response in brain tissues and may play a protective role in Alzheimer disease. 11 In the heart, we previously demonstrated that ABCG2 is expressed mainly in endothelial cells of mi-crovessels and plays a pivotal role in cardiac repair after myocardial infarction by promoting angiogenesis. 12 These findings suggest that ABCG2 may be important for tissue defense in various diseases.…”