Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders
Abstract
ABC (ATP-binding cassette) transporters represent one of the largest and most diverse superfamily of proteins in living species, playing an important role in many biological processes such as cell homeostasis, cell signaling, drug metabolism and nutrient uptake. Moreover, using the energy generated from ATP hydrolysis, they mediate the efflux of endogenous and exogenous substrates from inside the cells, thereby reducing their intracellular accumulation. At present, 48 ABC transporters have been identified in humans, which were classified into 7 different subfamilies (A to G) according to their phylogenetic analysis. Nevertheless, the most studied members with importance in drug therapeutic efficacy and toxicity include P-glycoprotein (P-gp), a member of the ABCB subfamily, the multidrug-associated proteins (MPRs), members of the ABCC subfamily, and breast cancer resistance protein (BCRP), a member of the ABCG subfamily. They exhibit ubiquitous expression throughout the human body, with a special relevance in barrier tissues like the blood-brain barrier (BBB). At this level, they play a physiological function in tissue protection by reducing or limiting the brain accumulation of neurotoxins. Furthermore, dysfunction of ABC transporters, at expression and/or activity level, has been associated with many neurological diseases, including epilepsy, multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. Additionally, these transporters are strikingly associated with the pharmacoresistance to central nervous system (CNS) acting drugs, because they contribute to the decrease in drug bioavailability. This article reviews the signaling pathways that regulate the expression and activity of P-gp, BCRP and MRPs subfamilies of transporters, with particular attention at the BBB level, and their mis-regulation in neurological disorders.
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In Alzheimer's disease, among 48 identified ATP-binding cassette transporters, P-glycoprotein is recognized as one of the beta-amyloid efflux pumps.
“In the AD context, from the 48 ABC transporters identified, the P-glycoprotein (P-gp) is recognized as one of the Aβ efflux pumps [19].”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [19]
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Wan, G., Huang, J., Wang, R., Liu, H., Wei, L., Liang, X., Li, F., Wang, Z., Gu, X., & Ruan, J. (2023) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2023.109737 · Cited by 4 · see citing works
- Authors
- Gil-Martins, E., Barbosa, D. J., Silva, V., Remião, F., & Silva, R.
- Affiliations
- Universidade do Porto (PT)
- Corresponding author
- Remião, Fernando
- Silva, Renata
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 213
- Pages
- 107554
- ISSN
- 0163-7258 (ISSN-L)
- OpenAlex
- W3017050326
- Cited by
- 152
- References
- 379
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 18 · 2023: 33 · 2022: 33 · 2021: 22 · 2020: 7
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação para a Ciência e a Tecnologia
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- ABC transporters, blood-brain barrier, P-glycoprotein, ABCG2, multidrug resistance protein, neurological disorders, epilepsy, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, drug resistance, signaling pathways, transporter regulation, drug bioavailability
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Central Nervous System Agents, Drug Resistance, Humans, Nervous System Diseases, ATP-Binding Cassette Transporters
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