ABCG2 reduces ROS-mediated toxicity and inflammation: a potential role in Alzheimer's disease.
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.
Shen
Shanshan
S
Department of Clinical Medicine, Southeast University, Nanjing, China.
Callaghan
Debbie
D
Juzwik
Camille
C
Xiong
Huaqi
H
Huang
Peilin
P
Zhang
Wandong
W
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D006427:Hemin / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007249:Inflammation / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020122:tert-Butylhydroperoxide / Q000633:toxicity
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C499706:CXCL2 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D016209:Interleukin-8; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); D006427:Hemin; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide