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Review
. 2024 Jun 18;5(6):101609.
doi: 10.1016/j.xcrm.2024.101609.

The impact of ATP-binding cassette transporters in the diseased brain: Context matters

Chrysiida Baltira  1 , Eleonora Aronica  2 , William F Elmquist  3 , Oliver Langer  4 , Wolfgang Löscher  5 , Jann N Sarkaria  6 , Pieter Wesseling  7 , Mark C de Gooijer  8 , Olaf van Tellingen  9
Affiliations
Review

The impact of ATP-binding cassette transporters in the diseased brain: Context matters

Chrysiida Baltira et al. Cell Rep Med. .

Abstract

ATP-binding cassette (ABC) transporters facilitate the movement of diverse molecules across cellular membranes, including those within the CNS. While most extensively studied in microvascular endothelial cells forming the blood-brain barrier (BBB), other CNS cell types also express these transporters. Importantly, disruptions in the CNS microenvironment during disease can alter transporter expression and function. Through this comprehensive review, we explore the modulation of ABC transporters in various brain pathologies and the context-dependent consequences of these changes. For instance, downregulation of ABCB1 may exacerbate amyloid beta plaque deposition in Alzheimer's disease and facilitate neurotoxic compound entry in Parkinson's disease. Upregulation may worsen neuroinflammation by aiding chemokine-mediated CD8 T cell influx into multiple sclerosis lesions. Overall, ABC transporters at the BBB hinder drug entry, presenting challenges for effective pharmacotherapy. Understanding the context-dependent changes in ABC transporter expression and function is crucial for elucidating the etiology and developing treatments for brain diseases.

Keywords: ABC transporters; P-glycoprotein; blood-brain barrier; brain diseases; breast cancer resistance protein.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests. Declaration of generative AI and AI-assisted technologies in the writing process During the revision of this work, the author(s) used ChatGPT as a tool to improve the grammar. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

Figures

None
Graphical abstract
Figure 1
Figure 1
CNS barriers The blood-CSF barrier (BCSFB) comprises the CP and arachnoid barrier cells. CSF is produced and expelled by the CP, flowing through the ventricles and subarachnoid space before reabsorption into the bloodstream via arachnoid villi. At the CP and the meninges endothelial cells are fenestrated. In these tissues, the barrier is formed by epithelial cells and arachnoid cells. At the BBB and the BSCB, endothelial cells form the barrier being connected by tight junctions. They are supported by astrocytes and pericytes, which generally are less abundant in the BSCB compared with the BBB, leading to lower tight junction expression and a potentially more permissive barrier. Created with BioRender.com together with Servier Medical Art under a Creative Commons Attribution 3.0 Unported License.
Figure 2
Figure 2
Graphical overview of cell type-specific changes in ABC transporter functionality in various brain diseases Changes for which robust experimental evidence exists are highlighted in green (up) or pink (down). Changes for which the literature has yet to produce conclusive results are depicted as gray. Created with BioRender.com.
Figure 3
Figure 3
Overview of the frequency of techniques employed and the extent of investigation into the various ABC transporters per studied disease (A and B) Diseases are ranked from least (CJD) to most-studied (brain tumors). Data are based on the list of studies provided in the supplemental tables. (A) Of all ABC transporters, the vast majority of studies investigate ABCB1, followed by ABCG2 and ABCC1 and, sporadically, ABCC2-5. (B) In general, while the applied techniques vary per disease, antibody-based methods predominate, except for PD and psychiatric disorders.
See this image and copyright information in PMC

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