Blood-brain barrier transport of amyloid beta peptides in efflux pump knock-out animals evaluated by in vivo optical imaging

Fluids and Barriers of the CNS

Danica Stanimirovic¹  Eric Brunette⁴  Dorothy Fatehi⁴  Ke Pei²  Aimee Jones⁴  Hong Liu⁴  Debbie Callaghan⁴  Huaqi Xiong³  Wandong Zhang¹ 

[1] Faculty of Medicine, University of Ottawa, Ottawa, Canada;Current address: The Hospital affiliated with the Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China;Current address: ApoPharma Inc., 100 Sussex Drive, Ottawa, Ontario, K1A 0R6, Canada;Human Health & Therapeutics Portfolio, National Research Council of Canada, Ottawa, Canada

关键词: Optical imaging;    Abcg2;    Abcb1a/b;    Mdr-1a/b P-glycoprotein;    Blood-brain barrier;    Aβ peptides;    Alzheimer’s disease;   

Others  :  806745
DOI  :  10.1186/2045-8118-10-13

 received in 2012-11-28, accepted in 2013-02-22,  发布年份 2013

【 摘 要 】

Background

Aβ transport (flux) across the blood-brain barrier (BBB) is thought to contribute to the pathogenesis of Alzheimer’s disease as well as to elimination of toxic amyloid from the brain by immunotherapy. Several BBB transporters have been implicated in Aβ exchange between brain parenchyma and the circulation, including efflux transporters P-glycoprotein/ABCB1 and BCRP/ABCG2. Here we describe an application of in vivo optical imaging methods to study Aβ transport across the BBB in wild-type or animals deficient in specific efflux transporters.

Methods/Design

Synthetic human Aβ_1-40 or scrambled Aβ_40-1 peptides were labeled with the near-infrared fluorescent tracer, Cy5.5. The free tracer or Cy5.5-labeled peptides were injected intravenously into Abcb1^-KO or Abcg2^-KO mice or their corresponding wild-type controls. The animals were imaged prospectively at different time points over a period of 8 hours using eXplore Optix small animal imager. At the end of the observation, animals were sacrificed by perfusion, their brains were imaged ex-vivo and sectioned for immunofluorescence analyses.

Discussion

After appropriate circulation time, the fluorescence concentration in the head ROI measured in vivo was close to background values in both wild-type and Abcb1^-KO or Abcg2^-KO mice injected with either free dye or scrambled Aβ_40-1-Cy5.5. In animals injected with Aβ_1-40-Cy5.5, the deficiency in either Abcb1 or Abcg2 resulted in significant increases in fluorescence concentration in the head ROIs 2 hours after injection compared to wild-type animals. Fluorescence decay (elimination rate) over 2–8 hours after injection was similar between wild-type (t_1/2 = 1.97 h) and Abcg2^-KO (t_1/2 = 2.34 h) and was slightly faster (t_1/2 = 1.38 h) in Abcb1^-KO mice. In vivo time-domain imaging method allows prospective, dynamic analyses of brain uptake/elimination of fluorescently-labeled compounds, including Aβ. Deficiency of either of the two major efflux pumps, Abcb1 and Abcg2, implicated in Aβ trafficking across the BBB, resulted in increased accumulation of peripherally-injected Aβ_1-40 in the brain.

【 授权许可】

   
2013 Zhang et al; licensee BioMed Central Ltd.

【 图 表 】

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