Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

Authors

DOI:

https://doi.org/10.17879/freeneuropathology-2021-3528

Keywords:

ABC transporter, ABCB1 (P-gp), ABCC1 (MRP1), ABCG2 (BCRP), ABCA1 (ABC1), ABCA2, ABCA5, ABCA7, Multitarget inhibitor (PANABC), Broad-spectrum modulator, Alzheimer’s disease, Amyloid-beta (Aβ / Abeta), Inhibition, Activation, Induction, Downregulation, PET Tracer (PETABC), Pattern analysis, Polypharmacology, Rational drug design and development

Abstract

Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer’s disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD. However, our understanding of other ABC transporters is limited, and most of the 49 human ABC transporters have been largely neglected as potential targets for novel small-molecule drugs. This is especially true for the ABCA subfamily, which contains several members known to play a role in AD initiation and progression. This review provides up-to-date information on the proposed functional background and pathological role of ABCA transporters in AD. We also provide an overview of small-molecules shown to interact with ABCA transporters as well as potential in silico, in vitro, and in vivo methodologies to gain novel templates for the development of innovative ABC transporter-targeting diagnostics and therapeutics.

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Author Biographies

Jens Pahnke, University of Oslo, University of Lübeck, University of Latvia

Department of Pathology
Section of Neuropathology
Translational Neurodegeneration Research and Neuropathology Lab
University of Oslo and Oslo University Hospital
Sognsvannsveien 20, 0372 Oslo, Norway;

LIED
University of Lübeck
Ratzeburger Allee 160, 23538 Lübeck, Germany;

Department of Pharmacology
Faculty of Medicine
University of Latvia
Jelgavas iela 1, 1004 Rīga, Latvia

Pablo Bascuñana, University of Oslo

Department of Pathology
Section of Neuropathology
Translational Neurodegeneration Research and Neuropathology Lab
University of Oslo and Oslo University Hospital
Sognsvannsveien 20, 0372 Oslo, Norway

Mirjam Brackhan, University of Oslo, University of Lübeck

Department of Pathology
Section of Neuropathology
Translational Neurodegeneration Research and Neuropathology Lab
University of Oslo and Oslo University Hospital
Sognsvannsveien 20, 0372 Oslo, Norway;

LIED
University of Lübeck
Ratzenburger Allee 160, 23538 Lübeck, Germany

Katja Stefan, University of Oslo

Department of Pathology
Section of Neuropathology
Translational Neurodegeneration Research and Neuropathology Lab
University of Oslo and Oslo University Hospital
Sognsvannsveien 20, 0372 Oslo, Norway

Vigneshwaran Namasivayam, University of Bonn

Department of Pharmaceutical and Cellbiological Chemistry
Pharmaceutical Institute
University of Bonn
An der Immenburg 4, 53121 Bonn, Germany

Radosveta Koldamova, University of Pittsburg

Department of Environmental and Occupational Health
School of Public Health, University of Pittsburgh
130 De Soto Street, Pittsburgh, PA 15261, United States of America

Jingyun Wu, University of Oslo

Department of Pathology
Section of Neuropathology
Translational Neurodegeneration Research and Neuropathology Lab
University of Oslo and Oslo University Hospital
Sognsvannsveien 20, 0372 Oslo, Norway

Luisa Möhle, University of Oslo

Department of Pathology
Section of Neuropathology
Translational Neurodegeneration Research and Neuropathology Lab
University of Oslo and Oslo University Hospital
Sognsvannsveien 20, 0372 Oslo, Norway

Sven Marcel Stefan, University of Oslo

Department of Pathology
Section of Neuropathology
Translational Neurodegeneration Research and Neuropathology Lab
University of Oslo and Oslo University Hospital
Sognsvannsveien 20, 0372 Oslo, Norway

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Published

2021-12-13

How to Cite

Pahnke, J., Bascuñana, P., Brackhan, M., Stefan, K., Namasivayam, V., Koldamova, R., Wu, J., Möhle, L., & Stefan, S. M. (2021). Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters. Free Neuropathology, 2, 33. https://doi.org/10.17879/freeneuropathology-2021-3528

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Reviews