Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimers disease patients: effect of polymorphisms in the ABCB1 geneReportar como inadecuado




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EJNMMI Research

, 2:57

First Online: 16 October 2012Received: 02 September 2012Accepted: 05 October 2012

Abstract

BackgroundP-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-Cverapamil 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.

MethodsThirty-two healthy subjects and seventeen patients with Alzheimer-s disease underwent 60-min dynamic R-Cverapamil PET scans. The binding potential of R-Cverapamil 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.

ResultsIn 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.

ConclusionsIn 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.

KeywordsBlood–brain barrier P-glycoprotein ABCB1 MDR1 Polymorphisms R-Cverapamil PET Electronic supplementary materialThe online version of this article doi:10.1186-2191-219X-2-57 contains supplementary material, which is available to authorized users.

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Autor: Daniëlle ME van Assema - Mark Lubberink - Patrizia Rizzu - John C van Swieten - Robert C Schuit - Jonas Eriksson - Phili

Fuente: https://link.springer.com/



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