QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 29, 2009, 29(17):5463-5475; doi:10.1523/JNEUROSCI.5103-08.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xiong, H. Articles by Zhang, W. Search for Related Content PubMed PubMed Citation Articles by Xiong, H. Articles by Zhang, W.

 Previous Article  |  Next Article 

Neurobiology of Disease
ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood–Brain Barrier for Aβ_1–40 Peptides

Huaqi Xiong,^1 * Debbie Callaghan,^1 * Aimee Jones,¹ Jianying Bai,¹ Ingrid Rasquinha,¹ Catherine Smith,¹ Ke Pei,¹ Douglas Walker,³ Lih-Fen Lue,³ Danica Stanimirovic,^1,2 and Wandong Zhang^1,2

¹Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada, ²Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, and ³Sun Health Research Institute, Sun City, Arizona 85351

Correspondence should be addressed to Dr. Wandong Zhang, Institute for Biological Sciences, National Research Council of Canada, 1200 Montreal Road, Building M54, Ottawa, ON K1A 0R6, Canada. Email: wandong.zhang{at}nrc-cnrc.gc.ca

Alzheimer's disease (AD) is characterized by accumulation and deposition of Aβ peptides in the brain. Aβ deposition in cerebrovessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Since Aβ can be transported across blood–brain barrier (BBB), aberrant Aβ trafficking across BBB may contribute to Aβ 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. Aβ alone or in combination with hypoxia/ischemia failed to stimulate ABCG2 expression in BBB endothelial cells; however, conditioned media from Aβ-activated microglia strongly induced ABCG2 expression. ABCG2 protein in AD/CAA brains interacted and coimmunoprecipitated with Aβ. Overexpression of hABCG2 reduced drug uptake in cells; however, interaction of Aβ_1–40 with ABCG2 impaired ABCG2-mediated drug efflux. The role of Abcg2 in Aβ transport at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of Cy5.5-labeled Aβ_1–40 or scrambled Aβ_40–1. Optical imaging analyses of live animals and their brains showed that Abcg2-null mice accumulated significantly more Aβ 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 Aβ from entering into brain. ABCG2 upregulation may serve as a biomarker of CAA vascular pathology in AD patients.

---

Received Sept. 24, 2008; revised Feb. 26, 2009; accepted March 18, 2009.

Correspondence should be addressed to Dr. Wandong Zhang, Institute for Biological Sciences, National Research Council of Canada, 1200 Montreal Road, Building M54, Ottawa, ON K1A 0R6, Canada. Email: wandong.zhang{at}nrc-cnrc.gc.ca

This article has been cited by other articles:

				C. D. Klaassen and L. M. Aleksunes Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation Pharmacol. Rev., March 1, 2010; 62(1): 1 - 96. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help