Brain Distribution of Dual ABCB1/ABCG2 Substrates Is Unaltered in a Beta-Amyloidosis Mouse Model.

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.

• Authors: Thomas Wanek, Viktoria Zoufal, Mirjam Brackhan, Markus Krohn, Severin Mairinger, Thomas Filip, Michael Sauberer, Johann Stanek, Thomas Pekar, Jens Pahnke, Oliver Langer
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 21 (Nov 03 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33153231 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Abcg2 protein, mouse
• Amyloid beta-Peptides
• Quinolines
• tariquidar

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (genetics, metabolism)
• Amyloid beta-Peptides (metabolism, toxicity)
• Amyloidosis (diagnostic imaging, metabolism, pathology)
• Animals
• Blood-Brain Barrier (metabolism)
• Brain (diagnostic imaging, metabolism)
• Disease Models, Animal
• Female
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Positron-Emission Tomography
• Quinolines (pharmacokinetics)
• Tissue Distribution