Emerging Role of ABC Transporters in Glia Cells in Health and Diseases of the Central Nervous System

Abstract

ATP-binding cassette (ABC) transporters play a crucial role for the efflux of a wide range of substrates across different cellular membranes. In the central nervous system (CNS), ABC transporters have recently gathered significant attention due to their pivotal involvement in brain physiology and neurodegenerative disorders, such as Alzheimer's disease (AD). Glial cells are fundamental for normal CNS function and engage with several ABC transporters in different ways. Here, we specifically highlight ABC transporters involved in the maintenance of brain homeostasis and their implications in its metabolic regulation. We also show new aspects related to ABC transporter function found in less recognized diseases, such as Huntington's disease (HD) and experimental autoimmune encephalomyelitis (EAE), as a model for multiple sclerosis (MS). Understanding both their impact on the physiological regulation of the CNS and their roles in brain diseases holds promise for uncovering new therapeutic options. Further investigations and preclinical studies are warranted to elucidate the complex interplay between glial ABC transporters and physiological brain functions, potentially leading to effective therapeutic interventions also for rare CNS disorders.

Keywords: ABC transporter; ABCA1; ABCA7; ABCB1; ABCC1; Alzheimer’s disease; EAE; Huntington’s disease; MDR1; MRP1; P-gp; astrocyte; demyelination; glia; metabolic diseases; microglia; multiple sclerosis; neurodegeneration; neuroinflammation; oligodendrocyte; rare diseases; steroid hormones.

Figure 1

Graphical overview of the role of ABC transporters in different brain cells, such as glia, neurons, and vascular cells (endothelia and pericytes). The different molecules fluxed out of the cells are represented by different symbols, which are explained in the legend (at the bottom of the figure). The transporters implicated in the efflux of these substances are represented in different colors and specified for each cell. The black arrows originate at the cells in which the effects take place and defined actions or effects of certain transporters are specified at the arrowheads.

Figure 2

Graphical overview of the role of ABC transporters in maintaining brain immune functions by regulating lymphocyte, monocyte, and dendritic cell functions, also in collaboration with astrocytes. The different molecules fluxed out of the cells are represented by different symbols, which are explained in the legend (at the bottom of the figure). The ABC transporters implicated in the efflux of these substances are represented in different colors and specified for each cell. The black arrows originate at the cells in which the effects take place, and defined actions or effects of certain transporters are specified at the arrowheads. Discontinued lines represent interaction between cells.

Figure 3

Graphical overview of the role of ABC transporters in microglia and macrophages. The different molecules fluxed out of the cells are represented by different symbols which are explained in the legend (at the bottom of the figure). The transporters implicated in the efflux of these substances are represented in different colors and specified for each cell. The black arrows originate at the cells in which the effects take place and defined actions of effects of certain transporters are specified at the arrowheads.

Figure 4

Clinical course of EAE in ABCB1a/b-ko mice (purple) compared to C57BL/6J control mice (grey). Data presented in the figure (mean +/− SEM) were statistically analyzed using a Mann–Whitney U test and Wilcoxon rank-sum test. * p < 0.05; ** p < 0.01. ABCB1-ko n = 15; C57BL/6J n = 13.

Figure 5

Clinical course of EAE in ABCC1-ko mice (blue) compared to C57BL/6J control mice (grey). Data presented in the figure (mean +/− SEM) were statistically analyzed using a Mann–Whitney U test and Wilcoxon rank-sum test. * p < 0.05; ** p < 0.01. ABCC1-ko n = 22; C57BL/6J n = 25.

Figure 6

Clinical course of EAE in ABCA7-ko mice (red) compared to C57BL/6J control mice (grey). Data presented in the figure (mean +/− SEM) were statistically analyzed using a Mann–Whitney U test and Wilcoxon rank-sum test. * p < 0.05; ** p < 0.01; *** p < 0.001. ABCA7-ko n = 31 until day 27 and n = 22 from day 28; C57BL/6J n = 34 until day 27 and n = 28 from day 28.