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. 2012 Oct 16;2(1):57.
doi: 10.1186/2191-219X-2-57.

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

Daniëlle Me van Assema  1 , Mark Lubberink, Patrizia Rizzu, John C van Swieten, Robert C Schuit, Jonas Eriksson, Philip Scheltens, Matthias Koepp, Adriaan A Lammertsma, Bart Nm van Berckel
Affiliations

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

Daniëlle Me van Assema et al. EJNMMI Res. .

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.

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Figures

Figure 1
Figure 1
Binding potential (BPND) of (R)-[11C]verapamil. Global BPND in healthy controls (HC, squares) and Alzheimer's disease patients (AD, triangles) as a function of T dose in (A) C1236T, (B) G2677T and (C) C3435T is shown. Mean BPND values and SD are given. (A) C1236T: In HC, BPND values for 0 T, 1 T and 2 T were 1.76 ± 0.45, 1.77 ± 0.45 and 1.79 ± 0.44, and in AD, the values were 1.74 ± 0.33, 2.11 ± 0.37 and 2.22 ± 0.13, respectively. (B) G2677T: In HC, BPND values for 0 T, 1 T and 2 T were 1.76 ± 0.45, 1.76 ± 0.44 and 1.81 ± 0.44, and in AD, the values were 1.74 ± 0.33, 2.11 ± 0.37 and 2.22 ± 0.13, respectively. (C) C3435T: In HC, BPND values for 0 T, 1 T and 2 T were 1.73 ± 0.49, 1.73 ± 0.44 and 1.88 ± 0.39, and in AD, the values were 1.56 ± 0.15, 2.17 ± 0.30 and 2.13 ± 0.27, respectively.
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