Open Access Original research

Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene

Daniëlle ME van Assema1*, Mark Lubberink2, Patrizia Rizzu3, John C van Swieten4, Robert C Schuit5, Jonas Eriksson2, Philip Scheltens1, Matthias Koepp6, Adriaan A Lammertsma5 and Bart NM van Berckel5

Author Affiliations

1 Department of Neurology and Alzheimer Center, VU University Medical Center, P.O. Box 7057, Amsterdam, 1007 MB, The Netherlands

2 PET Centre, Uppsala University Hospital, Uppsala, S 751 85, Sweden

3 Department of Clinical Genetics, VU University Medical Center, P.O. Box 7057, Amsterdam, 1007 MB, The Netherlands

4 Department of Neurology, University Medical Center Rotterdam, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands

5 Department of Nuclear Medicine and PET Research, VU University Medical Center, P.O. Box 7057, Amsterdam, 1007 MB, The Netherlands

6 Institute of Neurology, University College London, London, WC1N 3BG, UK

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EJNMMI Research 2012, 2:57  doi:10.1186/2191-219X-2-57

Published: 16 October 2012

Abstract

Background

P-glycoprotein is a blood–brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood–brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood–brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease.

Methods

Thirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction.

Results

In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T.

Conclusions

In Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood–brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.

Keywords:
Blood–brain barrier; P-glycoprotein; ABCB1; MDR1; Polymorphisms; (R)-[11C]verapamil; PET