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

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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https://hal-univ-artois.archives-ouvertes.fr/hal-02506588
Contributor : Virginie Justin-Labonne <>
Submitted on : Thursday, March 12, 2020 - 2:04:32 PM
Last modification on : Wednesday, March 25, 2020 - 3:43:13 PM

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Kati-Sisko Vellonen, Jouni Ihalainen, Marie-Christine Boucau, Fabien Gosselet, Théo Picardat, et al.. Disease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer’s Disease. Pharmaceutical Research, American Association of Pharmaceutical Scientists, 2017, 34 (12), pp.2652-2662. ⟨10.1007/s11095-017-2263-7⟩. ⟨hal-02506588⟩

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