Abstract
Background: ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) are co-localized at the blood-brain barrier (BBB), where they restrict the brain distribution of many different drugs. Moreover, ABCB1 and possibly ABCG2 play a role in Alzheimer’s disease (AD) by mediating the brain clearance of beta-amyloid (Aβ) across the BBB. This study aimed to compare the abundance and activity of ABCG2 in a commonly used β-amyloidosis mouse model (APP/PS1-21) with age-matched wild-type mice. Methods: The abundance of ABCG2 was assessed by semi-quantitative immunohistochemical analysis of brain slices of APP/PS1-21 and wild-type mice aged 6 months. Moreover, the brain distribution of two dual ABCB1/ABCG2 substrate radiotracers ([11C]tariquidar and [11C]erlotinib) was assessed in APP/PS1-21 and wild-type mice with positron emission tomography (PET). [11C]Tariquidar PET scans were performed without and with partial inhibition of ABCG2 with Ko143, while [11C]erlotinib PET scans were only performed under baseline conditions. Results: Immunohistochemical analysis revealed a significant reduction (by 29–37%) in the number of ABCG2-stained microvessels in the brains of APP/PS1-21 mice. Partial ABCG2 inhibition significantly increased the brain distribution of [11C]tariquidar in APP/PS1-21 and wild-type mice, but the brain distribution of [11C]tariquidar did not differ under both conditions between the two mouse strains. Similar results were obtained with [11C]erlotinib. Conclusions: Despite a reduction in the abundance of cerebral ABCG2 and ABCB1 in APP/PS1-21 mice, the brain distribution of two dual ABCB1/ABCG2 substrates was unaltered. Our results suggest that the brain distribution of clinically used ABCB1/ABCG2 substrate drugs may not differ between AD patients and healthy people.
| Original language | English |
|---|---|
| Article number | 8245 |
| Journal | International Journal of Molecular Sciences |
| Volume | 21 |
| Issue number | 21 |
| Pages (from-to) | 1-16 |
| Number of pages | 16 |
| ISSN | 1661-6596 |
| DOIs | |
| Publication status | Published - 01.11.2020 |
Funding
This research was funded by the Lower Austria Corporation for Research and Education (NFB) [grant number LS14-008, to T.W.], the Austrian Science Fund (FWF) [grant number I 1609-B24, to O. L.] and the Deutsche Forschungsgemeinschaft (DFG) [grant number DFG PA930/9, to J.P.]. The work of J.P. was also supported by the following grants: Deutsche Forschungsgemeinschaft/Germany (DFG PA930/12); Ministerium f?r Wirtschaft und Wissenschaft Sachsen-Anhalt/Germany (ZS/2016/05/78617); Leibniz Gemeinschaft/Germany (SAW-2015-IPB-2); Latvian Council of Science/Latvia (lzp-2018/1-0275); Nasjonalforeningen (16154), HelseS?/Norway (2016062, 2019054, 2019055); Barnekreftforeningen (19008); Norges forskningsr?det/Norway (251290, 260786 (PROP-AD), 295910). PROP-AD is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project and has received funding from the European Union?s Horizon 2020 research and innovation programme under grant agreement #643417 (JPco-fuND). Acknowledgments: The authors wish to thank Mathilde L?bsch for help in conducting the PET experiments and Alina Zwickl, Jaqueline Koller, Marlies Nemeth and Monika K?hteubl (University of Applied Sciences, Wiener Neustadt, Austria) for support with immunohistochemistry. Open Access Funding by the Austrian Science Fund (FWF). Funding: This research was funded by the Lower Austria Corporation for Research and Education (NFB) [grant number LS14-008, to T.W.], the Austrian Science Fund (FWF) [grant number I 1609-B24, to O. L.] and the Deutsche Forschungsgemeinschaft (DFG) [grant number DFG PA930/9, to J.P.]. The work of J.P. was also supported by the following grants: Deutsche Forschungsgemeinschaft/Germany (DFG PA930/12); Ministerium für Wirtschaft und Wissenschaft Sachsen-Anhalt/Germany (ZS/2016/05/78617); Leibniz Gemeinschaft/Germany (SAW-2015-IPB-2); Latvian Council of Science/Latvia (lzp-2018/1-0275); Nasjonalforeningen (16154), HelseSØ/Norway (2016062, 2019054, 2019055); Barnekreftforeningen (19008); Norges forskningsrådet/Norway (251290, 260786 (PROP-AD), 295910). PROP-AD is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project and has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement #643417 (JPco-fuND).
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
