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Disease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer’s Disease

Theme: Drug Discovery, Development and Delivery in Alzheimer’s Disease Guest Editor: Davide Brambilla

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Abstract

Purpose

Alzheimer’s disease (AD) may disturb functions of the blood-brain barrier and change the disposition of drugs to the brain. This study assessed the disease-induced changes in drug transporters in the brain capillaries of transgenic AD mice.

Methods

Eighteen drug transporters and four tight junction-associated proteins were analyzed by RT-qPCR in cortex, hippocampus and cerebellum tissue samples of 12–16-month-old APdE9, Tg2576 and APP/PS1 transgenic mice and their healthy age-matched controls. In addition, microvessel fractions enriched from 1-3-month-old APdE9 mice were analyzed using RT-qPCR and Western blotting. Brain transport of methotrexate in APdE9 mice was assessed by in vivo microdialysis.

Results

The expression profiles of studied genes were similar in brain tissues of AD and control mice. Instead, in the microvessel fraction in APdE9 mice, >2-fold alterations were detected in the expressions of 11 genes but none at the protein level. In control mice strains, >5-fold changes between different brain regions were identified for Slc15a2, Slc22a3 and occludin. Methotrexate distribution into hippocampus of APdE9 mice was faster than in controls.

Conclusions

The expression profile of mice carrying presenilin and amyloid precursor protein mutations is comparable to controls, but clear regional differences exist in the expression of drug transporters in brain.

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Abbreviations

AD:

Alzheimer’s disease

amyloid-β:

Aβ

BBB:

Blood-brain barrier

CB:

Cerebellum

CX:

Cortex

HC:

Hippocampus

wt:

Wild type

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Acknowledgments and Disclosures

This study was funded by Academy of Finland (Grant number 257386). Finnish Cultural Foundation is also acknowledged for financial support. KMK and TM acknowledges the funding from the Academy of Finland and Sigrid Juselius Foundation. We thank Dr. Aaro Jalkanen for advice in designing microdialysis experiment, Prof. Seppo Auriola for consultation in LC-MS/MS analysis and Lecturer Veli-Pekka Ranta for advice regarding pharmacokinetics. Mrs. Jaana Leskinen, Mrs. Leena Pietilä and Mrs. Lea Pirskanen are acknowledged for technical assistance. The authors declare that they have no conflict of interest. All applicable international, national and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Eastern Finland or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Authors and Affiliations

  1. School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, FI, Finland

    Kati-Sisko Vellonen, Jouni Ihalainen, Théo Picardat, Mikko Gynther, Markus M. Forsberg & Marika Ruponen

  2. Laboratoire de la barrière hémato-encéphalique (LBHE), University Artois, Lens, France

    Marie-Christine Boucau & Fabien Gosselet

  3. A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    Katja M. Kanninen, Tarja Malm & Jari Koistinaho

  4. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia

    Anthony R. White

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  1. Kati-Sisko Vellonen
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Correspondence to Kati-Sisko Vellonen.

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Vellonen, KS., Ihalainen, J., Boucau, MC. et al. Disease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer’s Disease. Pharm Res 34, 2652–2662 (2017). https://doi.org/10.1007/s11095-017-2263-7

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  • DOI: https://doi.org/10.1007/s11095-017-2263-7

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