ABCG2 is upregulated in Alzheimer's brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Abeta(1-40) peptides.
Alzheimer's disease (AD) is characterized by accumulation and deposition of Abeta peptides in the brain. Abeta deposition in cerebrovessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Since Abeta can be transported across blood-brain barrier (BBB), aberrant Abeta trafficking across BBB may contribute to Abeta accumulation in the brain and CAA development. Expression analyses of 273 BBB-related genes performed in this study showed that the drug transporter, ABCG2, was significantly upregulated in the brains of AD/CAA compared with age-matched controls. Increased ABCG2 expression was confirmed by Q-PCR, Western blot, and immunohistochemistry. Abcg2 was also increased in mouse AD models, Tg-SwDI and 3XTg. Abeta alone or in combination with hypoxia/ischemia failed to stimulate ABCG2 expression in BBB endothelial cells; however, conditioned media from Abeta-activated microglia strongly induced ABCG2 expression. ABCG2 protein in AD/CAA brains interacted and coimmunoprecipitated with Abeta. Overexpression of hABCG2 reduced drug uptake in cells; however, interaction of Abeta(1-40) with ABCG2 impaired ABCG2-mediated drug efflux. The role of Abcg2 in Abeta transport at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of Cy5.5-labeled Abeta(1-40) or scrambled Abeta(40-1). Optical imaging analyses of live animals and their brains showed that Abcg2-null mice accumulated significantly more Abeta in their brains than wild-type mice. The finding was confirmed by immunohistochemistry. These results suggest that ABCG2 may act as a gatekeeper at the BBB to prevent blood Abeta from entering into brain. ABCG2 upregulation may serve as a biomarker of CAA vascular pathology in AD patients.
Xiong
Huaqi
H
Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada.
Callaghan
Debbie
D
Jones
Aimee
A
Bai
Jianying
J
Rasquinha
Ingrid
I
Smith
Catherine
C
Pei
Ke
K
Walker
Douglas
D
Lue
Lih-Fen
LF
Stanimirovic
Danica
D
Zhang
Wandong
W
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018432:Drug Resistance, Multiple; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D009363:Neoplasm Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)