ABCG2 reduces ROS-mediated toxicity and inflammation: a potential role in Alzheimer's disease

Alzheimer's disease is characterized by accumulation and deposition of A beta peptides in the brain. A beta 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-kappa B 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 A beta production in cell models and on inflammatory signaling and A beta 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-kappa B 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-kappa B pathway. Abcg2 deficiency increased A beta deposition and NF-kappa B 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-kappa B signaling pathway in cell models and brain tissues and thus may play a potential protective role in Alzheimer's neuroinflammatory response.