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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.
J Neurosci. 2009 Apr 29; 29(17):5463-75.JN

Abstract

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.

Authors+Show Affiliations

Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario K1A 0R6, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19403814

Citation

Xiong, Huaqi, et al. "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." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 29, no. 17, 2009, pp. 5463-75.
Xiong H, Callaghan D, Jones A, et al. 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. J Neurosci. 2009;29(17):5463-75.
Xiong, H., Callaghan, D., Jones, A., Bai, J., Rasquinha, I., Smith, C., Pei, K., Walker, D., Lue, L. F., Stanimirovic, D., & Zhang, W. (2009). 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. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 29(17), 5463-75. https://doi.org/10.1523/JNEUROSCI.5103-08.2009
Xiong H, et al. 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. J Neurosci. 2009 Apr 29;29(17):5463-75. PubMed PMID: 19403814.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Xiong,Huaqi, AU - Callaghan,Debbie, AU - Jones,Aimee, AU - Bai,Jianying, AU - Rasquinha,Ingrid, AU - Smith,Catherine, AU - Pei,Ke, AU - Walker,Douglas, AU - Lue,Lih-Fen, AU - Stanimirovic,Danica, AU - Zhang,Wandong, PY - 2009/5/1/entrez PY - 2009/5/1/pubmed PY - 2009/6/6/medline SP - 5463 EP - 75 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 29 IS - 17 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/19403814/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_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=19403814 DB - PRIME DP - Unbound Medicine ER -