Free Neuropathology 2:33 (2021)

Review

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

Jens Pahnke^1,2,3, Pablo Bascuñana¹, Mirjam Brackhan^1,2, Katja Stefan¹, Vigneshwaran Namasivayam⁴, Radosveta Koldamova⁵, Jingyun Wu¹, Luisa Möhle¹, Sven Marcel Stefan¹

¹ Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway
² LIED, University of Lübeck, Lübeck, Germany
³ Department of Pharmacology, Faculty of Medicine, University of Latvia, Rīga, Latvia
⁴ Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, Bonn, Germany
⁴ Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America

Corresponding author:
Sven Marcel Stefan · Department of Pathology · Section of Neuropathology · Translational Neurodegeneration Research and Neuropathology Lab · www.pahnkelab.eu · University of Oslo and Oslo University Hospital · Sognsvannsveien 20 · 0372 Oslo · Norway
s.m.stefan@medisin.uio.no

Submitted: 07 September 2021

Accepted: 12 November 2021

Copyedited by: Biswarathan Ramani

Published: 13 December 2021

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.

INTRODUCTION

From MDR to neurodegeneration: ABC transporters in human disease

ABC transporters, Aβ proteins, and AD

PART I: STATUS QUO

ABCA transporters: Physiological function and implications for AD

ABCA1

ABCA2

ABCA3

ABCA4

ABCA5

ABCA6

ABCA7

ABCA8–ABCA10

ABCA12

ABCA13

Modulators of ABCA transporter function, trafficking, and regulation

Small-molecule interactors of ABCA transporters

Small-molecule regulators of ABCA transporters

PART II: PIPELINE DEVELOPMENT TO GAIN NOVEL DIAGNOSTICS AND THERAPEUTICS

In silico methodologies to predict novel lead structures

Structure-based drug design

Ligand-based drug design

In vitro methodologies to assess novel lead structures

Host system of ABCA transporters

Functional assessment of ABCA transporters

In vivo assessment of clinical candidates

Knock-out mouse models

RNAi models

Overexpression models

Humanized ABC transporter mouse models

Disease models

Imaging techniques

CONCLUDING REMARKS: WHERE DO WE GO FROM HERE?

APPENDIX

Abbreviations

5-FU - 5-fluorouracil, Aβ - amyloid-β, ABCA - ATP-binding cassette transporter subfamily A, ACAT - acyl coenzyme A cholesteryl acyl transferase, AD - Alzheimer’s disease, ADMA - asymmetric dimethylarginine, ADP - adenosine-diphosphate, ALS - amyotrophic lateral sclerosis, AMPK - cAMP-activated protein kinase, APOA1/E3/E4 - apolipoprotein A1/E3/E4, APP - amyloid precursor protein, ATP - adenosine-triphosphate, BBB - blood-brain barrier, BCSFB - blood-cerebrospinal fluid barrier, BHK - baby hamster kidney, BIG1 - brefeldin 1-inhibited guanine nucleotide exchange protein, BODIPY - 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene, cAMP - cyclic adenosine monophosphate, CFTR - cystic fibrosis transmembrane conductance regulator, CHO - Chinese hamster ovary, CNS - central nervous system, CPT-cAMP - 8-(4-chlorophenylthio)-cAMP, Cryo-EM - cryogenic electron microscopy, CSF - cer-ebral spinal fluid, DIDS - 4,4’-Diisothiocyano-2,2’-stilbenedisulfonic acid, EC₅₀ - half-maximal effect concentration, ECD - extracellular domain, ECGC - epigallocatechin gallate, ED₅₀ - half-maximal effective dose, EOAD - early-onset AD, FPD5 - fluorescigenic pyrazoline derivative 5, FXR - farnesoid-X-receptor, GFP - green fluorescent protein, GGPP - geranylgeraniol pyrophosphate, GSH - reduced glutathione, GWAS - genome-wide association study, HD - Huntington’s disease, HDAC2 - histone deacetylase 2, HDL - high-density lipoprotein, HMG-CoA-reductase - 3-hydroxyl-3-methyl glutaryl-coenzyme A reductase, HTS - high-throughput screening, IC₅₀ - half-maximal inhibition concentration, LAMP1 - lysosomal-associated membrane protein 1, LDLR - LDR receptor, lncRNA - long non-coding RNA, LOAD - late-onset AD, LTC₄ - leukotriene C4, LXR - liver-X-receptor, MDR - multidrug resistance, mRNA - messenger RNA, MS - multiple sclerosis, MSD - membrane-spanning domain, NBD - 7-nitro-2,1,3-benzooxadiazole or nucleotide binding domain, NDEA - N-nitrosodiethylamine, NEM - N-ethylmaleimide, (ox)LDL - (oxidized) low density lipoprotein, PCB29-pQ - 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone, PD - Parkinson’s disease, PDB - protein data bank, PG-J2 - prostaglandin J2, PMA - phorbol 12-myristate 13-acetate, PPAR - peroxisome proliferator-activated receptor, PRDX1 - peroxiredoxin 1, RAR - retinoic acid receptor, RNA - ribonucleic acid, RXR - retinoid-X-receptor, SAR - structure-activity relationships, shRNA - short-hairpin RNA, siRNA - small interfering RNA, SNP - single nucleotide polymorphism, SR-BI (Srb1) - scavenger receptor B1 (also HDL receptor), SREPB - sterol regulation element-binding protein, TKI - tyrosine kinase inhibitor, TKI - tyrosine kinase inhibitor, TM - transmembrane helix

INTRODUCTION

From MDR to neurodegeneration: ABC transporters in human disease

ABC transporters are membrane-bound transport proteins that are ubiquitously present in the human body.^1-4 They play a major role in determining the distribution of intrinsic and xenobiotic drugs between intra- and intercellular compartments.^5,6 The clinical relevance of ABC transporters became pronounced when their expression was correlated to cross-resistance of cancer cells to antineoplastic agents.^3,7-13 This phenomenon is called ‘multidrug resistance’ (MDR). However, despite enormous efforts and countless clinical trials to target these efflux pumps,^14-17 MDR is still a major unresolved obstacle in cancer chemotherapy. To date, most ABC transporters have been associated with MDR,^3,7-9,11,12 but only a small minority has been studied properly and can be addressed by small-molecule modulators.^18-22 Amongst these are ABCB1,^1,18-27 ABCC1,^{1,18,19,23,24,26,27} and ABCG2.^18,19,25

Apart from their role in multidrug-resistant cancer, many ABC transporters have been identified as key players in neurological disorders. Evidence for this includes their high abundance at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) in the central nervous system (CNS).^28-32 Additionally, their expression is altered in many pathological conditions in the brain.^28-30,33-40 Important players are, again, ABCB1,^{28-30,34-36,39-44} ABCC1,^{28-30,39,41,43,45} and ABCG2^{28,30,34,36,39-41,43}in diseases like AD,^28-30,41 amyotrophic lateral sclerosis (ALS),^34,36,44 encephalopathy,^45,46 epilepsy,^39,40 multiple sclerosis (MS),³⁵ and Parkinson’s disease (PD).^42,47 Furthermore, ABC transporters were also found to be associated with certain genetic neurological and psychiatric diseases such as Huntington’s disease (HD),³⁸ bipolar disorder,^48,49 depression,⁴⁸ or schizophrenia.^48,49 Table 1 summarizes the involvement of ABC transporters in neurological diseases.

Table 1. ABC transporters and related neurological and psychiatric diseases.

ABC transporters, Aβ proteins, and AD

Since 2001, ABC transporters have been implicated in AD pathogenesis.^{28-30,41,43,94,95} Specifically ABCB1,⁹⁴ ABCC1,⁹⁶ and ABCG2⁹⁷ have been suggested to directly transport amyloid-β (Aβ) proteins, being involved in Aβ clearance from the brain to the blood stream.^94,96,97 In light of the failure of the first immunological treatment studies,⁹⁸ it was already proposed that ABC transporter dysfunction could explain the clearance problem of Aβ.^99,100 Cerebral accumulation of Aβ proteins interferes with neuronal metabolite homeostasis and leads to interruption of cortico-cortical circuits and hampered synaptic communication. This results in an irreversible atrophy and degeneration of specific brain regions, which further causes behavioral, cognitive, and visuospatial impairments in the progression of AD.¹⁰¹

The most prominent ABC transporter subfamily involved in AD is the ABCA subfamily of cholesterol and phospholipid transporters, in which particularly ABCA1, ABCA2, ABCA5, and ABCA7 have been associated with AD.^{28-30,41,43,95,102} For ABCA1,^28,41,95,103 and specifically for ABCA7,^{28,41,95,104-107} genetic variant^{28,41,108-111} and genome-wide association studies (GWAS)^{28,41,106,107,112} have suggested that these transporters are risk factors in AD. These discoveries give the members of the ABCA subfamily a special standing within the group of AD-related ABC transporters.

Cholesterol metabolism in the context of AD has been discussed extensively before.^{95,102,104,105,113-116} The contribution of cholesterol and phosphilipid transport to membrane constitution, composition, fluidity, and lipid raft formation mediated by ABCA transporters has already been proposed,⁶ presenting a putative pharmacological target.¹¹⁷ Targeting cholesterol and lipid distribution impacts Aβ production by differential activities between α-, β-, and γ-secretases, but also amyloid precursor protein (APP) processing^106,118-122 and Aβ degradation.^{106,119,123-126} A contribution of ABCA transporters to Aβ clearance from the brain was also proposed,^{103,106,119,124,127} but not through direct Aβ transport.^128,129

Although ABCA transporters have been reviewed for the last two decades,^3,130,131 little is known about their specific contribution to AD pathogenesis and their mode of action. This is mainly due to a lack of small-molecules that can be used to track, study, and impact the function of these under-studied ABC transporters.

The present review consists of two parts: PART I provides the status quo of ABCA transporters in AD and small-molecule modulators – in particular intrinsic substrates, natural compounds, pharmacological drugs, and synthetic molecules – that have been reported to influence ABCA transporter function and expression; PART II outlines the necessary drug development pipeline for the discovery of novel lead structures as potential innovative diagnostics and therapeutics against AD. This pipeline includes cutting-edge in silico methodologies, established in vitro cell assays, and necessary in vivo models.

Collectively, this review contributes to a deeper understanding of small-molecule ligands that influence ABCA transporter function, potentially leading to the development of novel AD diagnostics and therapeutics.

PART I: STATUS QUO

ABCA transporters: Physiological function and implications for AD

ABCA transporters are ubiquitously present in the human body,^3,10,13 although differentially expressed.¹⁰ All of the 12 subfamily members have been associated with cholesterol and/or phospholipid transport and homeostasis,^3,13,132 except for ABCA4, which is primarily a transporter of retinoids.^133-138

In addition to the diseases listed in Table 1, ABCA transporters have been described as key proteins in several other human disorders, including neonatal respiratory distress syndrome (ABCA3),¹³⁹ chronic interstitial lung disease (ABCA3),¹⁴⁰ cataract-microcornea syndrome (ABCA3),¹⁴¹ hypertrichosis terminalis (ABCA5),¹⁴² or Harlequin ichtyosis (ABCA12).¹⁴³

However, one major clinical implication for ABCA transporters, particularly ABCA1, ABCA2, ABCA5, and ABCA7, relates to AD.^28,50,52,63 Their suggested roles in this major burdensome neurodegenerative disease as well as general physiological aspects are summarized in the following sections.

ABCA1

ABCA1 is the prototype of the ABCA subfamily,¹⁴⁴ was first identified in 1994, and is located on human chromosome 9.¹⁴⁵ The complete genomic sequence of human ABCA1 was reported in 2000. The ABCA1 gene spans 149 kb comprising 50 exons, and the resulting protein is 2261 amino acids long.¹⁴⁶ ABCA1 is located in the plasma membrane and is also present intracellularly in the endoplasmic reticulum and Golgi apparatus, where it mediates the efflux of cholesterol and phospholipids from intracellular compartments to extracellular lipid-free apolipoproteins, mainly apolipoprotein A1 (APOA1) and to a lesser extend APOA2 and APOE, to form high-density lipoprotein (HDL) particles.^3,147,148 The lipidation of APOA1 is preceded by ABCA1 dimerization.¹⁴⁹ ABCA1 thus represents the first and rate-limiting step in the reverse cholesterol transport pathway, which removes excess cholesterol from peripheral tissues via HDL and delivers it to the liver for conversion into bile acids and subsequent excretion. In contrast to peripheral tissues, the physiological role of ABCA1 in the brain, where it is expressed in all cell types, is not well defined.¹⁰³ It has been suggested that ABCA1 is required for cholesterol transport from glial cells to neurons via APOE, which is secreted by glial cells and serves as the main lipid acceptor in the brain.^103,125 In vitro and in vivo studies in Abca1 knock-out models demonstrated that ABCA1 is essential for normal APOE secretion and lipidation in the CNS.^150,151 Glial cells deficient for ABCA1 showed reduced lipid efflux with concurrent lipid accumulation as well as decreased APOE secretion, with APOE particles being small and poorly lipidated. In mice, Abca1 knock-out resulted in dramatically decreased brain levels of APOE. Moreover, examination of the hippocampi of Abca1-deficient mice revealed a decrease in neurite length and number of neurite segments and branches, pointing to an importance of ABCA1 for neurite integrity.¹⁵²

The major genetic risk factor for sporadic AD is the allelic state of the APOE genotype, with inheritance of the APOE4 allele markedly increasing disease risk.^153,154 Recently, Rawat et al. investigated how APOE4 affected ABCA1 expression and function in vitro in astrocytes.¹⁵⁵ The authors found that APOE4 decreased ABCA1 plasma membrane levels and increased ABCA1 co-localization with late endosomes via activation of ADP-ribosylation factor 6, thereby reducing cholesterol efflux and lipidation of APOE particles. They corroborated their findings in blood-cerebrospinal fluid (CSF) showing that CSF from homozygous carriers of the APOE4 allele was less efficient in stimulating ABCA1-mediated cholesterol efflux compared to CSF from homozygous carriers of the APOE3 allele.

A recent study assessed cholesterol efflux capacity of CSF by analyzing AD patients, non-AD patients, and control subjects.¹⁵⁶ The results demonstrated that ABCA1-mediated CSF-cholesterol efflux capacity was markedly reduced in AD but not in non-AD demented patients. However, this difference did not depend on APOE4 status. Interestingly, ABCA1-mediated CSF-cholesterol efflux capacity inversely correlated with total and phosphorylated protein tau, suggesting a link between the dysfunction of HDL-like particle in CSF and neurodegeneration.

Apart from the indirect link via APOE, a direct link between ABCA1 and AD has also been subject to investigation. Expression of hippocampal ABCA1 was elevated on both the mRNA and protein levels and was positively correlated with neuro-pathological changes and dementia severity in AD patients.¹⁵⁷ The authors of this study suggested that the observed upregulation of ABCA1 could be interpreted as a compensatory attempt to clear Aβ from the brain. Moreover, a variety of studies investigated associations between single nucleotide polymorphisms (SNP) in the ABCA1 gene and the risk for AD,^28,108-111 reporting inconclusive results.^95,103 A meta-analysis of several studies identified the ABCA1 rs2422493 (C477T) polymorphism as a risk factor for AD while no association was found for the rs2066718 (V771M) or rs1800977 (C14T) polymorphisms.¹¹¹ This risk effect for rs2422493 was confirmed in a recent genetic variant association study that, in contrast to the meta-analysis, also reported an increased AD risk for rs2066718 and a decreased AD risk for rs1800977.¹⁰⁹ Further genetic association studies and meta-analyses are necessary to search for potential associations between ABCA1 polymorphisms and AD risk.

In a recent AD GWAS, the rs1800978 polymorphism in the ABCA1 gene was identified as the lead SNP in a new genome-wide significant locus.¹⁵⁸ The association of genetic variants of the ABCA1 gene with AD risk was confirmed by exome sequencing data analysis from 32,558 individuals.¹⁵⁸ The study identified around 120 variants that have an increased frequency in early-onset AD (EOAD; 1.5%) and late-onset AD (LOAD; 1.1%) cases, compared to 0.5% of all controls. The data demonstrated that AD-association was mainly explained by extremely rare variants, but also by a smaller number of more common variants, e.g., N1800H.¹⁵⁹ Intriguingly, loss of function and missense variants in the ABCA1 gene were respectively associated with a 4.7-fold (95%CI 2.2-10.3) and 2.7-fold (95%CI 1.9-3.8) increased EOAD risk, and this was lower for LOAD cases suggesting that the burden of damaging ABCA1 variants was concentrated in younger AD patients.

Additionally, some long non-coding (lnc) RNAs such as lncRNA LOC286367 have been shown to affect ABCA1 expression.¹⁶⁰ LncRNA LOC286367 and ABCA1 are located on the same chromosome but are transcribed in opposite directions. A recent study demonstrated that LOC286367 reduces ABCA1 expression in THP-1 macrophages and increases the levels of proinflammatory cytokines.¹⁶⁰

The role of ABCA1 in Aβ deposition and clearance as well as in Aβ deposits-related memory deficits has been extensively investigated in APP-transgenic mouse models of AD. The lack of ABCA1 decreased brain APOE levels and either did not affect or increased Aβ load.^161-163 A recent study utilizing shotgun lipidomics experiments demonstrated a common APOE isoform-specific phospholipid signature between human APOE3/3 and APOE4/4 AD brains and lipoproteins isolated from astrocyte-conditioned media of APOE3 and APOE4 mice.¹⁶⁴ Interestingly, the lipoproteins derived from wild-type and Abca1^het mice had phospholipid content APOE3 > APOE4 > APOE3^het > APOE4^het suggesting that the combination of ABCA1 insufficiency and APOE4 genotype decreases APOE lipidation even further, thus aggravating APOE4 effect. These findings suggest that poorly lipidated APOE may promote Aβ aggregation.^129,161-163 In contrast, overexpression of ABCA1 in an APP-transgenic mouse model resulted in increased lipidation, albeit reduced brain levels of APOE and decreased Aβ load, implying that highly lipidated APOE may reduce Aβ aggregation propensity.¹²⁷ This is supported by findings of Deane et al., who showed that different APOE isoforms may differentially disrupt Aβ clearance from mice brains.¹⁶⁵ A stable isotope-labelling kinetic study in an APP-transgenic mouse model either lacking ABCA1 or overexpressing ABCA1 demonstrated increased APOE clearance in both Abca1 knock-out and ABCA1-overexpressing mice, but did not reveal any effect on Aβ clearance or production, suggesting that ABCA1 may regulate Aβ deposition by a mechanism other than altering Aβ metabolism.¹⁶⁶ In contrast, a study assessing the clearance of intracerebrally injected ¹²⁵I-Aβ from the brain reported that Abca1-deficiency decreased Aβ clearance in non-APP-transgenic mice.¹⁶⁷ Furthermore, knock-out of Abca1 was found to augment the dissemination of intracerebrally injected, brain-derived Aβ seeds in APP-transgenic mice.¹⁶⁷ Haplodeficiency of Abca1 led to decreased brain APOE levels and increased Aβ oligomer levels but did not affect Aβ deposition in APP-transgenic mice.¹⁶⁸ However, both haplodeficiency and homozygous knock-out of Abca1 aggravated cognitive deficits in APP-transgenic mice.^152,167,168 Lastly, the lack of one copy of Abca1 exacerbated memory deficits, decreased Aβ clearance, and increased Aβ load in APP-transgenic mice expressing human APOE4 but not in APP-transgenic mice expressing human APOE3.¹⁶⁹

ABCA2

ABCA2 is predominantly, but not exclusively, expressed in the brain, where it can be found in glial cells and neurons.^170-173 On the subcellular level, ABCA2 is located in endo- and lysosomal membranes, facilitating the sequestration of waste substances into intracellular vesicles.¹⁷² In addition, it is involved in myelin lipid transport, neural development, and macrophage activation.^30,174,175

Genetic variations of ABCA2 were identified as a risk factor for EOAD and sporadic AD.^52,176 These two studies showed a strong correlation between rs908832 and AD.^52,176 However, a later study could not find a link between this SNP and any form of AD.¹⁷⁷ In addition, ABCA2 mRNA expression was upregulated in AD patients compared to controls suggesting ABCA2 as a biomarker for differential diagnosis of AD.¹⁷⁸ Preclinical studies of ABCA2 suggested that this transporter modulates Aβ production via the LDL receptor (LDLR).^179,180 ABCA2 overexpression increased LDLR density, and LDLR deficiency has been described to enhance Aβ deposition.¹⁸¹ Chen et al. reported a co-localization of ABCA2 and Aβ as well as Aβ upregulation in cells overexpressing ABCA2. In addition, impairment of ABCA2 expression using small interfering RNA (siRNA) was accompanied by a decrease in Aβ production.¹⁸² Abca2 depletion has been shown to induce a shift from β- to α-secretases and thus, a reduction of APP processing by γ-secretase.¹⁸² Furthermore, ABCA2 has been proposed to play a role in Aβ production as it has been reported to upregulate sphingosine in murine cells and, therefore, to induce APP transcription.¹⁸³ However, another study in human cells could not confirm the modulation of Aβ production or cholesterol efflux by ABCA2.¹⁸⁴ Thus, further research on the role of ABCA2 in AD pathogenesis and its potential as a therapeutic target is necessary.

ABCA3

Despite its initial report of exclusive lung expression,¹⁸⁵ ABCA3 is also found in other tissues including the brain.^186,187 Within the brain, the highest levels of ABCA3 were found in oligodendrocytes.¹⁸⁸

ABCA3 plays a role in producing surfactants in the lung, suggesting that the transporter may also be involved in lipid metabolism in the brain, specifically phosphatidylcholine and phosphatidylglycerol transport. Interestingly, phosphatidylcholine has also been discussed in the context of AD.¹⁸⁹ A genetic study revealed that mutations in ABCA3 can also cause cataract-microcornea syndrome, a rare congenital malformation of the eye.¹⁴¹ The actual implications of the potential connection between altered ABCA3 functionality and AD need to be addressed in future studies.

ABCA4

ABCA4 is mainly expressed in the retina with very little presence in other tissues of the CNS.¹⁹⁰ ABCA4 mutation causes Stargardt disease, characterized by macular dystrophy, retinal alterations, and lipofuscin accumulation.^{60,61,190,191} Other retinal diseases, such as fundus flavimaculatus, retinitis pigmentosa, or cone-rod dystrophy, have also been associated with mutations of ABCA4.^55,57,58,192 ABCA4 is expressed in brain capillary endothelial cells, as well.¹⁹³ However, no link between ABCA4 and AD has been suggested to date.

ABCA5

ABCA5 is a little-known member of the ABCA subfamily expressed mainly in skeletal muscle with unknown function in the brain.¹⁹⁴ Studies in peripheral tissues suggest that the function of ABCA5 is associated with cellular lipid metabolism.¹⁹⁵ Abca5 knock-out in mice induced signs of lysosomal storage disease in the heart and the thyroid gland.¹³¹

In the brain, ABCA5 is expressed in neurons and, to a lesser extent, in microglia, astrocytes, and oligodendrocytes.¹⁹⁵ Fu et al. showed that ABCA5 stimulated cholesterol efflux in neurons and induced a decrease in Aβ production probably affecting APP processing but not its expression.¹⁹⁵

ABCA6

ABCA6 is ubiquitously expressed with high levels in liver, lung, heart, brain, and ovaries. This transporter is probably involved in macrophage lipid homeostasis as it is upregulated during macrophage differentiation and is responsive to cholesterol treatment.¹⁹⁶ Although certain missense variants of ABCA6 have been correlated with blood cholesterol levels,¹⁹⁷ no link between ABCA6 and AD has yet been found.

ABCA7

ABCA7 was first identified in the year 2000, and is located on human chromosome 19.^198-200 Analysis of ABCA7 mRNA expression levels has shown that this transporter is mainly confined to the brain and the immune system.³ Due to its high homology to ABCA1 (54%),²⁰⁰ ABCA7 was first hypothesized to play an important role in lipid trafficking, mediating cholesterol and phospholipid efflux. ABCA7 actively transports phosphatidylcholine, phosphatidylserine, and sphingomyelin from the cytoplasm to the exocytoplasmic leaflet of membranes.^198,199,201 However, in contrast to ABCA1, ABCA7 generates only small HDL particles.²⁰² Recent research has shown that lipid trafficking by ABCA7 plays a secondary role. Studies in Abca7 knock-out models have demonstrated that ABCA7 is involved in the phagocytotic activity of macrophages and fibroblasts^198,203-205 but not in cell cholesterol release.^206-208

In 2011, Hollingworth et al. identified the ABCA7 gene as an AD risk locus.^198,209 In multiple studies, variants of ABCA7 have been associated with an increased risk of developing AD.^198,210-212 In 2015, Steinberg et al. reported that rare loss-of-function variants of ABCA7 confer a risk of AD in Icelanders (odds ratio: 2.12; P = 2.2 ∙ 10^-13), and found a similar association in study groups from Europe and the United States (combined odds ratio: 2.03; P = 6.8 ∙ 10^-15).²¹³ In particular, the rare AD-related polymorphism rs200538373 was associated with an AD risk odds ratio of 1.9.²¹⁰ These studies suggest that reduced levels of ABCA7 may increase the risk of AD. Nonetheless, it is not clear how these polymorphisms affect ABCA7 function and contribute to AD progression. Increased levels of ABCA7 expression were described in AD patients and were also positively correlated with cognitive decline.^198,211 This finding is consistent with Abca7 mRNA transcription levels in J20 mice.¹²³ The increase of ABCA7 may be a compensatory defense mechanism that is insufficient to stop disease progression. Furthermore, the rs3764650G allele has been associated with increased neuritic plaques in human patients^198,214 and a limitation of the neuroprotective effects of exercise intervention.²¹⁵ These studies support a potential protective role of ABCA7 in AD. To date, three potential roles have been identified for ABCA7 contribution to AD: APP processing, immune response, and lipid metabolism.

Chan et al. proposed an inhibitory effect of ABCA7 on Aβ deposition after showing in vitro inhibition of Aβ production independent of β-secretase activity.¹²⁰ Other authors proposed that ABCA7 is not directly linked to Aβ production, but rather through lipid metabolism as ABCA7 mediates the transport of lipids across the BBB and ABCA7 loss of function may alter cholesterol transport by decreasing APOE secretion and ABCA1 expression. This alteration in cholesterol metabolism can also contribute to AD development.²¹⁶ However, Abca7 knock-out induced an increase of Aβ load with no difference in clearance rate and an increase of β-secretase expression. On the other hand, ABCA7 overexpression led to diminished Aβ production and improved cognitive function.^217,218

Nevertheless, ABCA7 is highly expressed in phagocytic cells, including macrophages and microglia, suggesting a role of the transporter in phagocytosis.^188,198 Phagocytosis is crucial to maintain brain homeostasis. Indeed, ineffective phagocytosis may induce neuroinflammation, which is a risk factor in AD. In addition, microglial cells are involved in phagocytosis and degradation of Aβ. Thus, an involvement of ABCA7 in microglial phagocytosis of Aβ may explain the contribution of this transporter to AD pathogenesis. In AD patients, increased ABCA7 transcription has been found in areas with plaques but not in unaltered regions such as the cerebellum.¹²³ This increase in transcription was paralleled by microglia recruitment supporting the contribution of ABCA7 to microglia-mediated phagocytosis of Aβ. In addition, Abca7 knock-out mice showed a reduced microglia response after intracerebral Aβ injection.¹²³ Kim et al. demonstrated an increased Aβ load in J20/A7 knock-out mice compared to J20 mice, potentially due to an altered phagocytic function.^124,198 Furthermore, it has recently been shown that Abca7 haplodeficiency disturbs the microglial immune response and causes enhanced Aβ accumulation in microglia, probably due to alterations in endolysosomal trafficking.²¹⁹

Last, a new hypothesis has emerged recently, assigning ABCA7 a prominent role in the altered lipidostasis hypothesis in AD.¹⁰⁴ The authors of this study proposed the existence of a neurodegenerative lipid that is naturally removed by ABCA7. A loss of ABCA7 function due to the described polymorphisms might accelerate accumulation of this lipid, inducing Aβ aggregation. In fact, a link between cholesterol metabolism and ABCA7-mediated phagocytosis has been reported, which may also explain the protective properties of statin treatment in the development of AD.^{105,198,203,220}

Despite recent findings, the role of ABCA7 in AD pathogenesis remains unclear. According to in vitro and preclinical research, it may be associated with phagocytic activity by microglia, which could be linked to cell cholesterol metabolism.^105,198,203 Thus, further investigation is required to reveal the role of ABCA7 in AD pathogenesis and its potential use as a therapeutic target for this neurodegenerative disease.

ABCA8–ABCA10

So far, no obvious role of ABCA8–10 has been elucidated for AD, neurodegenerative diseases, nor any human disease. However, several potential intrinsic substrates of ABCA8 have been identified.^10,221,222 Furthermore, a significant number of ABCA transporter modulators have been identified on this target.²²² Hence, ABCA8 represents a good model system for the development of potential therapeutics targeting other ABCA transporters taking the scarce knowledge on this transporter subclass into account.

ABCA12

ABCA12 is expressed predominantly in the epidermis, and its main function is the transport of lipids.²²³ It is hypothesized that ABCA12 plays a role in skin lipid homeostasis. Mutations in this gene are associated with lamellar ichthyosis type 2 and Harlequin ichthyosis.^143,224,225 However, a Japanese study investigated common polymorphisms of ABCA12 and did not find an association with sporadic AD.²²⁶

ABCA13

ABCA13 is the largest ABC transporter with 576 kDa.²²⁷ It has been reported to be highly expressed in the brain as well as in peripheral tissues.²²⁷ A very small study found reduced neuroinflammation and altered ABCA13 expression in post mortem analyses of brains from patients with Lewy body dementia.⁶⁴ In addition, increased ABCA13 expression has been reported after stroke in mice.⁶⁷ Furthermore, two studies showed enhanced ABCA13 mRNA expression in schizophrenic patients after different antipsychotic treatments, suggesting a role of this transporter in psychiatric disorders.^48,65,66 However, no association between ABCA13 and AD has been found.

Modulators of ABCA transporter function, trafficking, and regulation

‘Modulation’ is a widely used term to summarize actions of small-molecules that have been reported to alter ABCA transporter function, trafficking, and/or regulation. Modulators can be divided into ‘interactors’ and ‘regulators’.

Interactors summarize compounds that directly bind to ABCA transports, which can have either inhibiting or activating effects on the transporters. Substrates are also included in this category. In terms of ABCA transporters, however, a direct interaction of these agents with their target(s) has in most cases not yet been comprehensively proven. Therefore, compounds that are believed to directly interact with ABCA transporters extend the category of interactors. Figure 1 represents the most prominent interactors of ABCA transporters and provides additional information about their mode of modulation.

Regulators are compounds that change ABCA transporter expression (transcription and/or translation) in terms of induction and/or downregulation. In addition, compounds that regulate ABCA transporter trafficking can be included into the category of regulators, as this effect was often observed as ‘pseudo-protein increase’ at the cell membrane. Figure 2 depicts the most prominent regulators of ABCA transporters including proposed mode of modulations.

It must be stated that the term ‘inhibitor’ and ‘activator’ are often misused in the literature, as in most cases studies describe a downregulation or induction. In the present review, this mislabeling has been taken into account and the present review and the respective compounds have been allocated into the correct groups. As established earlier,^23,24 the compounds are sorted according to their origin: (i) intrinsic substrates and substrate-like molecules, (ii) (other) natural compounds, (iii) pharmacological drugs, (iv) high-throughput screening-(HTS)-derived candidates, as well as (v) compounds from synthetic/medicinal chemistry approaches. Figure 3 gives a general overview of specific interactors and their postulated mode of modulation. Table 2 summarizes all modulators of ABCA1, the most studied ABCA transporter, while Table 3 summarizes all known modulators in terms of the other ABCA transporters. The stated concentration values are indicators of bioactivities of the respective compound and are strongly dependent on the testing system utilized. Hence, the respective data must be interpreted with caution.

Small-molecule interactors of ABCA transporters

Endo- and xenobiotic substrates

The most genuine interactors of ABCA transporters are intrinsic substrates of these transporters. These include cholesterol (Figure 1) and other sterol derivatives,^{10,221,222,228} but also phospholipids (Figure 1), sphingolipids^228,229 and retinoids (e.g., all-trans-retinal; Figure 1).^133-138 In addition, certain intrinsic molecules were demonstrated to interact with ABCA transporters, in particular with ABCA1²³⁰ and ABCA8.^10,221,222 α-tocopherol (vitamin E) was demonstrated to be transported by ABCA1,²³⁰ and to interfere with ABCA1 regulation.²³¹ The sterol derivatives estradiol-β-glucuronide, estrone sulfate, and taurocholic acid (Figure 1), but also the physiological substrate leukotriene C4 (LTC₄), the natural compound ochratoxin A, as well as the chemical p-amino hippuric acid were discovered as (potential) ABCA8 substrates.^10,221,222 Specifically the ABCA8-mediated taurocholate export from various human pancreatic cancer cell lines was suggested as the major mechanism behind gemcitabine resistance in these cells,²²¹ which was corroborated in HEK293 cells stably expressing ABCA8.¹⁰

In addition, a small body of evidence suggests that ABCA2 and ABCA3 contribute to the subcellular sequestration of certain antineoplastic agents into endo- and lysosomes.^232-235 These agents include cytarabine (ABCA3),²³⁵ daunorubicin (ABCA3),^232,233,235 etoposide (ABCA3),²³⁵ imatinib (ABCA2 and ABCA3; Figure 1),^234,236 mitoxantrone (ABCA3),²³⁵ and vincristine (ABCA3; Figure 1).²³⁵ Furthermore, several antineoplastic agents were described to have less effect when ABCA2 was overexpressed in vitro^171,237,238 and in vivo.²³⁹ For example, the anticancer drug estramustine (Figure 1) was effluxed from ABCA2-overexpressing human ovary carcinoma cells, which were less susceptible to estramustine treatment than the sensitive cell line.^171,238 Antisense nucleotide treatment against ABCA2 re-sensitized the carcinoma cells, further demonstrating a role for ABCA2 in mediating drug efflux.²³⁸ Furthermore, Abca2 knock-out mice had elevated estradiol and estrone levels when treated with estramustine.²³⁹ A similar effect in terms of susceptibility and re-sensitization was observed for ABCA3-mediated transport of miltefosine in Leishmania,²⁴⁰ doxorubicin resistance in acute myeloid leukemia cells,²³⁷ and cisplatin as well as paclitaxel resistance in several lung cancer cell lines.²⁴¹

Table 2. Currently known modulators of ABCA1.

^a u.c. = unspecified concentration
^b u.d. = unspecified dose

Strikingly, ABCA2 co-localized with the lysosomal-associated membrane protein 1 (LAMP1) – an endolysosomal marker – as well as the fluorescence probe dansyl-estramustine. This co-localization indicates a direct sequestration of this antineoplastic drug into endo- and/or lysosomes.¹⁷¹ On the other hand, the susceptibility of ABCA3-overexpressing CCRF-CEM leukemia cells to the antineoplastic agents cytarabine, methotrexate (Figure 1), vincristine, but also the anti-inflammatory drug dexamethasone, was reduced compared to their parental counterparts.²⁴² Taken together, ABCA2 and ABCA3 are contributors to MDR, and the number of potential ABCA2 and ABCA3 substrates may be even higher than currently suggested.

Interestingly, missense mutations of ABCA4 were associated with chloroquine- and hydroxychloroquine-associated retinopathy,²⁴³ although contradictory studies exist.²⁴⁴ A direct interaction was postulated, however, not proven. Nevertheless, these results suggest chloroquine and hydroxychloroquine as potential ABCA4 substrates.

Table 3. Currently known modulators of ABCA transporters other than ABCA1.

^a apart from cholesterol and/or phospholipids
^b u.c. = unspecified concentration
^c u.d. = unspecified dose

Inhibitors

To date, the number of small-molecules that (are believed to) directly interact with ABCA transporters is very low. For example, only 14 inhibitors can be found in the literature regarding the most studied prototype of ABCA transporters, ABCA1.^245-248 Only four of these inhibitors are associated with half-maximal inhibition concentrations (IC₅₀),^245,249 which is the ‘golden surrogate’ to evaluate and judge inhibitory activities of small-molecules. The following section will highlight these small-molecules as well as inhibitors of other ABCA transporters.

ABCA1

Glibenclamide and 4,4’-diisothiocyano-2,2’-stilbenedisulfonic acid (DIDS)

As outlined above, ABCA1 is the most studied and understood ABCA transporter, although its particular role in neurodegenerative diseases in general^51,103 – and in AD in particular – is not well understood.^{28-30,43,95,102} However, over time, several agents were found to impact ABCA1 transport function. The most prominent examples are glibenclamide and DIDS (both Figure 1), which were first shown to inhibit ABCA1 in 1997.^247,248 These drugs blocked the ABCA1-mediated ¹²⁵I efflux from murine peritoneal macrophages²⁴⁷ as well as human ABCA1-transfected Xenopus laevis Oocytes.²⁴⁸ Glibenclamide and DIDS inhibited the ABCA1-mediated transport of cholesterol and other sterols as well as phospho- and sphingolipids. Thus, these agents became the ‘standard ABCA1 inhibitors’ and have frequently been used in ABCA1 studies ever since.^229,250-269 Glibenclamide and DIDS were preferred over other discovered ABCA inhibitors, such as bumetanide, diphenylamine 2-carboxylic acid, flufenamic acid, furosemide, and bromosulfophthaleine.²⁴⁸ Specifically glibenclamide was rigorously evaluated regarding its mechanism of action. It was demonstrated that glibenclamide prevented cross-linking of ¹²⁵I-marked APOA1 to ABCA1,^267,270 not interfering with ABCA1 location at the cell surface.²⁶⁷ In essence, glibenclamide and DIDS may play a significant role in the development of future modulators of ABCA transporters in general.

Probucol and cyclosporine A

Less prominent but also well characterized are the antilipidemic drug probucol^246,271-278 and the immunosuppressant cyclosporine A^{245,249,258,279-281} (both Figure 1). Probucol was demonstrated to reduce the cholesterol efflux from different ABCA1-overexpressing murine and human macrophages,^275-278 and total lipid release (cholesterol + phospholipids) from human WI-38 fibroblasts.²⁴⁶ Vice versa, probucol increased accumulation of free cholesterol, cholesterol esters, phosphatidylcholine, and sphingomyelin in human fibroblasts.²⁴⁶ Additionally, probucol was reported to prevent cell surface-specific binding of ¹²⁵I marked APOA1 to ABCA1.^246,278 Similarly, this effect has already been demonstrated for glibenclamide before.^267,270 Interestingly, it was shown that total ABCA1 protein levels were increased after exposure to probucol due to decreased degradation.^246,275 This qualifies probucol also as a stabilizer. However, as its inhibiting effect is far more pronounced, we have included it as an inhibitor here.

The immunosuppressant cyclosporine A has been characterized as an ABCA1 inhibitor in multiple studies.^{245,249,258,279-281} This inhibition was shown to be direct through a radiolabeled variant of cyclosporine A and purified ABCA1.²⁴⁵ Cyclosporine A not only functionally inhibited ABCA1-mediated cholesterol and phospholipid efflux,^245,249 and caused intracellular accumulation of cholesterol,²⁵⁸ but also inhibited the ABCA1-dependent binding of Alexa 546- or ¹²⁵I-labeled APOA1,^245,249 as demonstrated for glibenclamide^267,270 and probucol^246,278 before. Interestingly, toxicity assays demonstrated that cyclosporine A negated the positive effect of an ABCA1 inducer on cell viability when cells were exposed to Aβ proteins.²⁸⁰ This was confirmed in vivo in C57BL/6 mice that had reduced HDL levels.²⁴⁹ Interestingly, cyclosporine A was shown to decrease ABCA1 turnover, increasing its presence at the cell surface by a factor of two as demonstrated with a GFP-labeled ABCA1 variant,²⁴⁹ suggesting a similar mode of inhibition as for probucol.²⁷⁵ Thus, as for probucol,^246,275 cyclosporine A also appears to have a stabilizer function,²⁷⁵ but is included in the current section due to its pronounced inhibitory role. Morevover, the cyclosporine A analog valspodar (PSC833) inhibited direct binding of radiolabeled cyclosporine A to ABCA1, revealing that valspodar also acts as an ABCA1 inhibitor.^245,282 Furthermore, several other calmodulin antagonists inhibited ABCA1-mediated cholesterol efflux and binding of APOA1.²⁴⁵ These include pimecrolimus,²⁴⁵ sirolimus,²⁴⁵ and tacrolimus,²⁴⁵ suggesting these molecules as potential scaffolds for the development of future ABCA1 modulators.

Other ABCA1 inhibitors

In terms of other small-molecules that were suggested to inhibit ABCA1 function, BLT-4 has been demonstrated to inhibit cholesterol and phospholipid export from adipocytes and macrophages,²⁵⁵ and to decrease cholesterol efflux from ABCA1-transfected HEK293 cells. BLT-4 was also shown to inhibit ¹²⁵I-marked APOA1-binding to ABCA1,²⁷⁰ as demonstrated for glibenclamide,^267,270 probucol,^246,278 and cyclosporine.^245,249

Other ABCA transporters

While ABCA1 can be considered a less-studied ABC transporter with certain knowledge about its function and interfering small-molecules,¹⁸ all other ABCA transporters belong to the group of under-studied ABC transporters that cannot be addressed by small-molecules with very rare exceptions.¹⁸

One rare example is ABCA8. Using the Xenopus laevis Oocytes model in vitro testing system,²⁴⁸ Tsuruoka et al. reported inhibitors of this transport protein.²²² While digoxin, probenecid, and verapamil (all Figure 1) could be identified as very weak inhibitors of ABCA8-mediated estradiol-β-glucuronide transport, dofequidar (MS-209), ochratoxin A, and verlukast (MK-571; Figure 1) were discovered as moderately potent inhibitors.²²² In addition, glibenclamide was also suggested to (partially) inhibit ABCA8 function.²⁶⁶

Activators

Although activators of ABC transporters have been reported, as for example, for ABCB1²³ and ABCC transporters,^23,283-288 these reports are somewhat scarce compared with other classified modulators of ABC transporters. In terms of A subclass ABC transporters, no small-molecule activators are known. However, it is well established and has been extensively demonstrated that ABCA1 activity depends on (co)-administration of HDL and/or APOA1.¹¹⁷ HDL and APOA1 are not small-molecules but peptides, and therefore fall outside of the scope of the present review. Similarly, it has been shown in several reports that HDL-mimics consisting of 26 amino acids are able to increase ABCA1-mediated transport.²⁸⁹ Although these molecules are also not small-molecules, the scarceness of activators of ABCA transporters warrants the inclusion of these middle-sized molecules here.

In 2004, structural elements of APOA1 were discovered to promote ABCA1-mediated cholesterol efflux.²⁹⁰ In 2007, Vedhachalam et al. discovered that the C-terminus of APOE promoted ABCA1-mediated efflux from murine J774.A1 macrophages.²⁹¹ The latter discovery led to the development of two short-length peptides, ATI-5261 and CS-6253, consisting of 26 amino acids each.²⁸⁹ Their amino acid sequences expressed in single-letter code are EVRSKLEEWFAAFREFAEEFLARLKS²⁸⁹ and EVCitSKLEEWLAALCitELAEELLACit-LKS (Cit = citrulline),²⁹² respectively, which is of particular interest for the development of novel lead structures. Both peptides increased ABCA1-mediated cholesterol and phospholipid transport in murine and human macrophages.^289,292 Interestingly, CS-6253 decreased ¹²⁵I-labed APOA1 binding to ABCA1,²⁹² as demonstrated for glibenclamide,^267,270 probucol,^246,278 cyclosporine A,^245,249 and BLT-4²⁷⁰ before. However, CS-6253 was shown to compete with APOA1 to promote ABCA1-mediated transport.²⁹² Both ATI-5261 and CS-6253 have a high practical relevance regarding AD and other neurodegenerative diseases, as these agents demonstrated in vivo efficacy.^289,293 ATI-5261 treatment of high fat diet-fed Apoe knock-out mice decreased cholesterol levels in both plasma and feces and reduced atherosclerotic lesions.²⁸⁹ For CS-6253, a reduction of Aβ₄₂ levels and tau protein phosphorylation in transgenic humanized APOE4 mice was demonstrated, which was accompanied by improved cognitive functions.²⁹³ Interestingly, an elevation of ABCA1 protein was also observed in treated mice.²⁹³ Indeed, a stabilization and/or induction may also have contributed to the observed effects. However, the proven direct binding of these agents suggested that activation takes place as the major mode of action. Nonetheless, CS-6253 has not been tested in AD mouse models so far, and being a peptide, it would not be suitable for oral application in patients.

Small-molecule regulators of ABCA transporters

The herein discussed regulators interfere with ABCA transporter expression and/or trafficking. Important representatives are depicted in Figure 2 and additional information is given in terms of their mode of modulation. Since many different pathways are involved in ABCA transporter regulation, Figure 3 provides a general overview of participating proteins and protein families in terms of the most studied ABCA transporter, ABCA1.

Inducers

ABCA1 - LXR and RXR pathways

Given the findings in AD mouse models with knock-out of ABCA1/Abca1 or overexpression of ABCA1, upregulating ABCA1 activity may be a therapeutic strategy for decreasing Aβ pathology in AD. ABCA1 is under the transcriptional control of the nuclear receptors liver-X-receptor (LXR) and retinoid-X-receptor (RXR),^294-296 which can be targeted by small-molecule agonists of LXR and RXR to induce ABCA1 expression (Figure 3). Numerous studies reported that treatment of APP-transgenic mice with LXR or RXR agonists decreased Aβ load^126,297-301 and/or improved cognitive impairment.^{126,297,298,300} Other studies reported cognitive improvement without significant changes in Aβ load in APP-transgenic mice treated with LXR agonists.^302,303 LXR and RXR agonists have already been described extensively as potential therapeutics in the literature, also with respect to AD.³⁰⁴ The present review will focus on those agonists that were reported in clear association with ABCA1.

Oxysterols and retinoic acids

22-(R)-hydroxycholesterol (Figure 2) has been established as the natural gold standard for ABCA1/Abca1 induction through LXR activation,^{122,205,249,252,259,262-264,268,277,278,305-315} while 9-cis retinoic acid (Figure 2) became the natural gold standard for RXR activation.^{122,245,249,259,262,264,277,278,309,311,313,316} The inducing effects were described both on ABCA1/Abca1 mRNA^{122,205,252,263,264,305,307-311,313,315-317} and ABCA1 protein levels.^{122,252,263,264,306,309-311,316,318}

Other oxysterols like 4-hydroxycholesterol, 20-(S)-hydroxycholesterol, 22-(S)-hydroxycholesterol, 24-hydroxycholesterol, 24-(S)-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol itself also induced ABCA1/Abca1 mRNA^{205,305,313,315,319-327} and ABCA1 protein levels.^321,328 The increase in ABCA1 protein was functionally confirmed by an enhanced cholesterol^{305,306,313,315,318} and phospholipid efflux,^311,318 as well as reduced total cholesterol influx.³⁰⁵ Specifically 22-(R)-hydroxycholesterol and cholesterol induced both LXRA/Lxra and LXRB/Lxrb.^310,321 Additionally, cholesterol also induced murine peroxisome proliferator-activated receptor γ (PPAR-γ) mRNA (Pparg),³²¹ which represents an important alternative pathway for ABCA1/Abca1 induction. Furthermore, 24-(S)-hydroxycholesterol reduced in parallel the sterol regulation element-binding protein 2 (SREBP2) gene expression (Srebp2).³²³ The SREB protein family also represents another important pathway in ABCA1/Abca1 regulation.

The 9-cis-retinoic acid derivative all-trans¬-retinoic acid (ATRA) significantly increased ABCA1/Abca1 mRNA and ABCA1 protein content in murine and human macrophages, which was paralleled by increased LXRA mRNA levels in human macrophages.³²⁹ This increase resulted in a subsequently enhanced cholesterol efflux from murine macrophages. ATRA is an agonist of the retinoic acid receptor (RAR),³²⁹ which is in close relation to the RXR receptor and a potential target of retinoic acid derivatives.

TO901317 and GW3965

The synthetic gold standard and most studied ABCA1/Abca1 inducer in the literature is TO901317 (often referred to as ‘T0901317’; Figure 2).^{205,245,250,252,259,260,262,264,271,272,279,280,282,308,310,317,319,322,324,326,328-345} TO901317 targeted both the LXR α^{250,310,328,330,332,335,337-340,342} and LXR β pathways,^{250,310,338,342} which correlated to ABCA1/Abca1 induction on mRNA and ABCA1 protein levels.^{205,250,279,282,310,319,322,324,326,328,330-335,337-340,342,343} In addition, an induction of SREBP1C/Srebp1c has also been observed.^336,342 Functionally, TO901317 increased cholesterol efflux,^{250,259,260,262,264,282,319,324,329,331,342} decreased intracellular Aβ content, and increased Aβ secretion from different murine brain cells.^126,345 Further, it reduced Aβ_25-35-mediated toxicity toward cells by induction of Abca1.²⁸⁰ In addition, TO901317 mitigated memory deficits in high-fat diet-fed APP23 mice, reducing both plaque and soluble Aβ protein levels.³⁴⁴ Besides, TO901317 reduced methionine-(homocysteine)-induced atherosclerotic lesions in Apoe knock-out C57BL/6 mice.³³⁵ These findings were paralleled by an increase of Abca1 mRNA and ABCA1 protein content,³³⁵ suggesting a potential relevance of TO901217 in AD therapy, although it must be taken into account that LXR activators, in particular TO901317, were demonstrated to have severe side effects in mice, such as neutropenia, hypertriacylglycerolemia, hepatic triacylglycerol accumulation, and hepatic steatosis.^271,346,347

The second most common synthetic LXR-α and LXR-β agonist is GW3965 (Figure 2).^{255,272,317,319,321,334,348-352} GW3965 increased mRNA^{317,319,321,348,349,351,352} and protein levels^255,272,351 in different ABCA1-expressing cells. Functionally, increased Abca1 mRNA and ABCA1 protein levels correlated with enhanced cholesterol efflux.^255,351 Strikingly, exposure of murine BV2 microglia to GW3965 reduced Aβ₄₂ levels due to an enhanced degradation of Aβ₄₂,¹²⁶ suggesting that ABCA1 contributes to general Aβ degradation. Finally, GW3965 significantly increased Abca1 transcription in C57BL/6 mice,^334,351 and improved contextual memory as well as Aβ pathology in TG2576 mice,¹²⁶ emphasizing its high relevance in AD therapy.

ABCA1 - other LXR agonists and inducers

Sterane and sterane-like natural compounds

Several sterane derivatives were demonstrated to target LXR-α and LXR-β activation^{253,307,310,353} and/or LXRa/Lxra and LXRB/Lxrb upregulation,^{330,332,354,355,356,357} resulting in induction of ABCA1/Abca1. Celastrol,^330,332 digoxin,²⁵³ fuco-sterol,³⁰⁸ certain gypenosides,³⁵⁴ ouabain,²⁵³ platy-codin D,³⁵⁵ saikosaponin A,³⁵⁶ 24-(S)-saringosterol,³⁰⁷ 24-(S)-stigmast-5-ene-3β,24-diol,³⁰⁷ taxarasterol,³⁵³ testosterone,³⁵⁷ and TR1³¹⁰ increased ABCA1/Abca1 mRNA^{307,308,310,330,332,353,354,356,357} and/or ABCA1 protein content^{310,253,353,354,355,357} leading to an enhanced efflux of cholesterol in vitro^{253,308,330,332} and decreased intracellular cholesterol and/or phospholipid levels in vitro^{330,332,354,356,357} and in vivo in mice.²⁵³ The effect of fucosterol was comparable to that of the standard ABCA1/Abca1 inducer TO901317.³⁰⁸ A correlation to SREBP1(C) upregulation^308,307,357 and SREBP1 protein expression³⁵⁷ could be determined in case of fucosterol,³⁰⁸ 24-(S)-saringosterol,³⁰⁷ 24-(S)-stigmast-5-ene-3β,24-diol,³⁰⁷ and testosterone.³⁵⁷ In case of celastrol, the regulation of intracellular cholesterol was pinned to an activation of autophagy^330,332 and lipophagy,³³⁰ which are processes that may be associated with Aβ degradation.

Flavonoids

The flavonoids naringenin,³³⁹ quercetin,³⁵⁸ and vitexin³⁵⁹ increased ABCA1/Abca1 mRNA^339,359 and ABCA1 protein levels^339,360,358 by induction of LXRA/Lxra mRNA^358,359 and LXR-α protein.^339,360 The effect of naringenin and the standard ABCA1/Abca1 inducer TO901317 were additive. Naringenin was shown to be dependent on the cAMP-activated protein kinase (AMPK) regulation (AMPK), as well as SREBP1C regulation.³³⁹ The AMPK pathway is another very important regulator of ABCA1 expression. Functionally, cholesterol efflux from human^339,360 and murine³⁶⁰ macrophages was increased in the presence of naringenin.^339,360 In vivo, naringenin and quercetin induced Abca1³⁶⁰ and ABCA1,^361,362 as well as ABCA1-mediated cholesterol transport,³⁶⁰ which was reflected in reduced atherosclerotic lesions in the aorta of high-fat diet-fed C57BL/6 mice.³⁶⁰ In terms of quercetin, a protein increase of LXR-α and PPAR-γ was observed.³⁶¹

Chalcones, the precursors of flavonoid biosynthesis, were also demonstrated to intervene with ABCA1 expression. The chalcone derivatives 1h,³⁶³ 1m,^363,364 and 1m-6³⁶⁴ were demonstrated to increase ABCA1 mRNA and ABCA1 protein levels in THP-1 macrophages,^363,364 which was accompanied by an increase in LXRA mRNA and LXR-α protein levels.³⁶³ The intracellular lipid content was decreased, while the cholesterol efflux was increased after exposure of THP1-cells to 1m-6.³⁶⁴ In addition, SREBP1 mRNA was increased by 1m-6,³⁶⁴ and aortic atherosclerotic plaques were reduced in Ldlr knock-out C57BL/6 mice.³⁶⁴

Polyphenols and diterpenoid natural compounds

The polyphenols kuwanon G,³⁶⁵ paeonol,²⁵² the Celtis biondii-derived compound ethyl 2,4,6-trihydroxybenzoate,³⁴² and the diterpenoid farnesin³⁶⁶ increased ABCA1/Abca1 mRNA^{252,342,365,366} and ABCA1 protein^{252,342,365,366} content in an LXR-α-^252,366 and LXR-β-dependent³⁴² manner, which in parallel reduced cholesterol content²⁵² and increased ABCA1-mediated cholesterol efflux in various cell lines.^252,342,366 In vivo, farnesin increased ABCA1 protein content and cholesterol efflux in Apoe knock-out C57BL/6 mice in primary peritoneal macrophages and the aorta, which was reflected in reduced atherosclerotic plaques.³⁶⁶

Other natural compounds

Several other natural compounds induced ABCA1/Abca1 targeting LXR-α and LXR-β activation^{256,272,256,349,367} and/or LXRA/Lxra and LXRB/Lxrb induction.^{331,348,350,368,369,370,371,372,373,374} The garlic ingredient allicin,³⁵⁰ the alkaloid berberine,²⁵⁶ the coumarin bergapten A,³⁶⁸ certain Pestalotiopsis neglecta-derived chromene derivatives,³⁴⁸ the Rheum palmatum-derived anthra-quinone danthron,³⁶⁹ the lacton 1,6-O,O-diacetylbritannilactone,³⁷¹ epigallocatechin gallate (EGCG),³⁷⁰ the glycoside geniposide,³⁷⁵ the vegetable ingredient phenethyl isothiocyanate,³⁷³ the carotenoid lycopene,³⁷² the Pestalotiopsis neglecta-derived hydroquinone pestalotioquinoside C,³⁴⁹ the alkaloid rutaecarpine,³⁶⁷ selenium,³⁷⁴ the macro-lactone soraphene A,²⁷² and vitamin D₃³³¹ led to increased ABCA1/Abca1 mRNA^{256,272,331,348,369,256,367,370,372,373} and ABCA1 protein^{256,272,331,349,350,368,369,256,367,371,373,374} content in vitro^{331,349,350,369,375,374} and in vivo,^{368,369,370,371,372,373} enhancing cellular cholesterol efflux^{256,272,256,367,369} and reducing intracellular cholesterol con-tent.^{331,350,369,256,367,375,372,374} Danthron also increased AMPK protein levels,³⁶⁹ while EGCG downregulated Srebp1 mRNA and SREBP1 protein content.³⁷⁰ Lycopene induced Ppara mRNA in tobacco carcinogen- and cigarette smoke-exposed ferrets,³⁷² while isothiocyanate induced Pparg mRNA as well as PPAR-γ protein content in high fat diet-fed C57BL/6 mice.³⁷³ The inducing effects on ABCA1 expression of vitamin D₃ and TO901317 were additive.³³¹ Danthron, EGCG, geniposide, and rutaecarpine demonstrated also reduced atherosclerotic lesions in Apoe knock-out C57BL/6 mice,^{369,370,375,367} and isothiocyanate ameliorated the aortic injury of the high-fat diet in the same mice.³⁷³

Pharmacological drugs

Several pharmacological drugs also demonstrated an induction of ABCA1/Abca1 through LXR-α and/or LXR-β, including the α₁-blocker doxazosin,³⁷⁶ the 5-HT₃ receptor antagonist ondansetron,²⁷⁹ and the anesthetic propofol.³⁷⁷ Consequently, increased Abca1 mRNA^279,376 and ABCA1 protein^279,376 levels were observed in human^279,377 and murine^279,376 macrophages^376,377 as well as astrocytes.²⁷⁹ Functionally, ondansetron induced APOE efflux,²⁷⁹ while propofol led to increased cholesterol efflux.³⁷⁷ In addition, propofol increased PPARG mRNA and PPAR-γ protein content in human macrophages.³⁷⁷

Furthermore, certain antineoplastic agents interfered with ABCA1 expression via LXR-α and/or LXR-β. Doxorubicin demonstrated an Lxr activation with subsequent induction of Abca1 mRNA and ABCA1 protein in vitro and in vivo.²⁵⁰ Functionally, doxorubicin elevated cholesterol export in vitro. It was shown that intra- and extracellular levels of cholesterol, cholesterol precursors, and several oxysterols were elevated after exposure to doxorubicin. These precursors included lathosterol, lanosterol, and desmosterol, while the oxysterols included 7-α-hydroxycholesterol, 7-β-hydroxycholesterol, 7-ketocholesterol, 24-hydroxycholesterol, and 27-hydroxycholesterol. The authors suggested that doxorubicin exposure induced cholesterol metabolism subsequently leading to an induction of ABCA1. Besides, idarubicin augmented also Abca1 mRNA levels in vitro.

Synthetic compounds and HTS hits

Other synthetic compounds have been shown to induce ABCA1/Abca1 expression by LXR-α and/or LXR-β induction. The polymer pyrrole-imidazole-polyamide activated a promoter region for Abca1 expression and thereby increased cholesterol and lipid efflux from RAW264.7 cells.³⁷⁶ The authors confirmed their findings in vivo, revealing increased Abca1 mRNA and ABCA1 protein content in peripheral blood mononuclear cells and the liver in C57BL/6 mice after exposure to pyrrole-imidazole-polyamide.

In addition, the LXR agonist LXR623 induced ABCA1 mRNA and ABCA1 protein levels in two human renal adenocarcinoma cell lines³³⁴ as well as Abca1 mRNA levels in vivo in C57BL/6 mice.³⁷⁸ This induction was reflected in reduced intracellular cholesterol and triglyceride levels.

It must be noted that several other synthetic LXR-α and LXR-β agonists induced Abca1 expression in vivo: AZ1–AZ9, AZ876, BMS-852927, F1, WAY254011.³⁷⁸ Finally, an HTS approach discovered two LXR-α and LXR-β agonists as novel small-molecule ABCA1/Abca1 inducers: F4 and M2.³¹⁹

Synthetic approaches

A few synthetic approaches have aimed toward the development of ABCA1/Abca1 inducers.^{271,336,352,379-382} The cholic acid analog 14b,³³⁶ the thiophene derivative CL2-57,²⁷¹ as well as derivatives of N-benzothiazolyl-2-benzene-sulfonamide,³⁷⁹ ginsenoside,³⁵² and rutaecarpine,³⁶⁷ all induced ABCA1/Abca1 mRNA^336,352,381 and ABCA1 protein^{271,336,379,381} content in vitro^271,336,379 and in vivo,²⁷¹ targeting the LXR-α/LXR-β pathway³⁵² by activation²⁷¹ or induction³³⁶ of LXR-α/LXRA/Lxra and/or LXR-β/LXRB/Lxrb. In vitro, cholesterol efflux increased^379,381 and intracellular cholesterol as well as lipid content were reduced,^336,352 while plasma and liver triglycerides levels were reduced in vivo in high fat diet-fed C57BL/6 mice.²⁷¹ Interestingly, 14b induced farnesoid-X-receptor (FXR) transcription (Fxr),³³⁶ and CL2-57 inhibited RXR-β, PPAR-γ, and PPAR-δ,²⁷¹

Finally, Singh et al. described highly potent LXR-α and LXR-β agonists with effect at concentrations in the nanomolar range.³⁸² The described podocarpic acid derivatives have not yet been demonstrated to induce ABCA1. However, these compounds were designated as potential ABCA1 inducers by the authors,³⁸² and their high potency makes them interesting candidates for further evaluation.

Such synthetic approaches should be highlighted,^{271,336,352,379-382} as chemical derivatization of ABCA1 inducers and elucidation of their structure-activity relationships (SAR) have not yet been comprehensively assessed. More reports are needed to gain innovative molecules that can be considered clinically for the treatment of various ABCA1-related diseases.

ABCA1 - other RXR agonists and inducers

In terms of synthetic RXR agonists, the 4-chromanon derivatives SPF1 and SPF2 increased Abcb1 mRNA and ABCA1 protein levels and lowered Aβ_25–35-mediated cell toxicity in vitro.²⁸⁰ The same effect was observed for the RXR agonist bexarotene,²⁸⁰ an FDA approved drug against T-cell lymphoma-related cutaneous malformations. Bexarotene was used as a standard inducer of ABCA1/Abca1 via the RXR pathway in several studies.^{271,272,280,319,380} Induction of Abca1 mRNA and ABCA1 protein levels was maximal for bexarotene in combination with TO901317.²⁸⁰ Bexarotene is of particular practical relevance as a potential treatment against AD due to its in vivo effects. In different AD mouse models, bexarotene increased Abca1 mRNA and ABCA1 protein levels, but also reduced cerebral load of Aβ and hyperphosphorylated protein tau, which is also a histological marker in AD and other dementias.^297,383 This prospect led to synthetic bexarotene derivatives, specifically Z10 and Z36.³⁸⁰ Both candidates induced ABCA1 protein expression by RXR-α activation and reduced Aβ burden in the hippocampus of female APP/PS1 mice. This coincided with an enhanced ABCA1 protein expression in BV2 cells.

Moreover, the pan-RAR agonist TTNPB also increased ABCA1 protein content in murine macrophages in an RXR-α-dependent manner. However, the effect was generally smaller compared to the effect of ATRA.³²⁹ Finally, a combination of the LXR and RXR agonists RO0721957 and RO0264456 increased ABCA1 mRNA in THP-1 macrophages accompanied by increased cholesterol efflux.³⁸⁴ RO0264456 was demonstrated to increase ABCA1 protein content in combination with TO901317.²⁶⁰

ABCA1 – protein kinase C (PKC), AMPK, and p38 mitogen-activated protein kinase (MAPK)

An alternative approach to induce ABCA1 is targeting the PKC pathway (Figure 3). PKC agonists were extensively used to induce ABCA1/Abca1 mRNA and ABCA1 protein levels.^{230,248,249,255,265,266,273,278,289-292,384-387} Prominent PKC agonists include cAMP³¹³ as well as synthetic derivatives, such as 8-Bromo-cAMP (8-Br-cAMP; Figure 2),^{230,249,255,266,290,292} 8-(4-chlorophenylthio)-cAMP (CPT-cAMP),^273,291,384 and dibutyryl-cAMP.^385-387 The observed effects ranged in the same order of magnitude as the combination of 22-(R)-hydroxycholesterol and 9-cis-retoic acid.³¹³ The increase in ABCA1/Abca1 mRNA and ABCA1 protein levels was reflected in an enhancement of ABCA1-mediated cholesterol and phospholipid efflux,^249,255,386 and increased APOA1 binding to murine RAW264.7 macrophages.^385-387 Similar observations have been made for the PKC stimulant phorbol 12-myristate 13-acetate (PMA), which induced ABCA1 protein expression and ABCA1-mediated cholesterol and phospholipid release.³⁸⁶ PMA is also the standard substance used to differentiate human monocytic leukemia cells into THP-1 macrophages –
a standard host system for ABCA transporter evaluation.^{231,245,249,256,268,272,275,292,308,310,312-316,321,328,335,338,}
​^{339,341,342,360,363,364,366,377,384,388-397}

Regarding the AMPK pathway (Figure 3), the natural compound curcumin induced ABCA1/Abca1 mRNA^338,388 and ABCA1 protein levels^388,394 as well as cholesterol efflux^338,388,394 in THP-1^338,388,394 and RAW264.7³⁹⁴ macrophages, which was also mediated through LXR-α activation.³³⁸ However, these LXR-α activating effects were much more pronounced in combination with the gold standard TO901317.³³⁸ Other AMPK-targeting agents are A 769662 and metformin,³⁹⁸ which induced ABCA1/Abca1,³⁹⁸ LXRA/Lxra,^396,398 and LXRB/ Lxrb^396,398 in human³⁹⁸ and murine (primary) macrophages,³⁹⁸ leading to increased cholesterol efflux.³⁹⁶

Concerning the MAPK pathway (Figure 3), the sterane glycoside ginsenoside compound K increased Abca1 mRNA and ABCA1 protein levels in murine macrophages, reducing intracellular lipid content and promoting autophagy.³⁹⁹ These effects were pinned to a negative impact on the MAPK pathway. Finally, a synthetic inhibitor of MAPK, SB203580, was shown to induce ABCA1 protein in combination with the above mentioned geniposide in vitro in murine macrophages.³⁷⁵

ABCA1 - the PPAR Pathway

Another well-known approach to induce ABCA1 involves the PPAR pathway (Figure 3).^{268,272,295,309,315,321,326,
327,337,343,395,400-409} Certain PPAR/Ppar inducers and/or PPAR activators have been described above, as these modulators also have effects on the LXR pathway.^{321,361,372,373,377}

Several natural compounds target the PPAR pathway, such as the flavonoids homo-eriodictyol,⁴⁰² hesperetin-7-O-β-_D-glucopyrano-side,⁴⁰² scutellarein,⁴⁰³ and the antimycotic trichostatin A.⁴¹⁰ These compounds increased Abca1⁴⁰² and Pparg⁴⁰² mRNA as well as ABCA1,^402,410 PPAR-α,⁴⁰³ and PPAR-γ^402,410 protein levels in vitro^402,410 and in vivo.⁴⁰³ Decreased intracellular cholesterol levels were also observed.⁴⁰² Trichostatin A reduced aortic atherosclerotic plaques in high-fat diet-fed Apoe knock-out mice,⁴¹⁰ and an upregulation of ABCA1, PPAR-γ, and LXR-α/β protein levels was observed in aortic cells as well as peritoneal macrophages.⁴¹⁰

Several drugs and drug-like PPAR agonists were revealed to induce ABCA1/Abca1 mRNA and/or ABCA1 protein content, including the PPAR-α agonists fenofibrate,^326,400,404 pemafibrate (K 877),⁴⁰⁵ Wy14643,^268,343 and RPR-5,²⁶⁸ as well as the PPAR-γ agonists efatutazone,³³⁷ pioglitazone,^{272,309,326,395,407} pitavastatin,³⁴³ prostaglandin J2 (PG-J2),^268,327 rosiglitazone (Figure 2),^{268,309,315,408,409} troglitazone,²⁶⁸ and GW7845,³¹⁵ but also the broad-spectrum PPAR-α, PPAR-β, and PPAR-γ agonist bezafibrate^268,327 and the multitarget PPAR-α, PPAR-γ, and PPAR-δ agonist tetradecylthioacetic acid.⁴⁰¹ This induction was observed for ABCA1/Abca1 mRNA^{268,315,343,401,405} as well as ABCA1 protein levels,^{268,337,343,395,405,409} and was functionally confirmed by increased cholesterol efflux.^268,315 A connection between the PPAR and LXR pathways has also been drawn,^{268,326,327,337,400} highlighting the importance of both pathways for ABCA1/Abca1 induction. Furthermore, fenofibrate had a positive impact on both the LXR-α and AMPK pathways⁴⁰⁰ Certain PPAR agonists have been used as standard inducers of Abca1, e.g., pioglitazone⁴⁰⁷ and rosiglitazone.⁴⁰⁸

Synthetic PPAR agonists were also reported to induce ABCA1.⁴⁰⁶ The benzothiazole derivative E3317 dose-dependently increased ABCA1/Abca1 mRNA and ABCA1 protein levels though PPAR-γ activation in several cell lines.⁴⁰⁶ This was reflected in decreased cholesterol efflux and reduced intracellular cholesterol content. Finally, a molecular docking approach to discover novel PPAR agonists has yielded GQ-11, which induced Abca1 mRNA in livers of C57BL/6 Ldlr knock-out mice.⁴⁰⁷

ABCA1 - the 3-hydroxyl-3-methyl glutaryl-(HMG)-CoA-reductase pathway

Other targets for ABCA1/Abca1 induction are the 3-hydroxyl-3-methylglutaryl-(HMG)-CoA-reduc-tase and cellular cholesterol synthesis (Figure 3).^318,343 Several HMG-CoA-reductase inhibitors such as atorvastatin (Figure 2),^330,343,362 fluvastatin,^312,411 mevastatin (compactin),³¹⁸ pitavastatin,^318,343 and simvastatin^312,343 increased ABCA1/Abca1 mRNA^312,343 and ABCA1 protein levels,^362,411 as well as ABCA1-mediated cholesterol efflux.³¹⁸ These data are surprising, as one might expect the loss-of-function of an enzyme in the cholesterol synthesis pathway to induce a decrease of ABCA1, preventing cholesterol depletion from cells.^314384,412 Conversely, the overproduction of cholesterol leads to the opposite effect, as demonstrated for mevalonate, which is a building block of cholesterol synthesis⁴¹³ and has been demonstrated to increase ABCA1/Abca1 mRNA^312,314 and to abrogate Abca1 downregulation.³¹² Pitavastatin addressed SREBP-driven promotor regions upregulating Abca1 mRNA levels,³⁴³ and atorvastatin reduced atherosclerotic plaques in Apoe knocked-out C57BL/6 mice by induction of ABCA1 protein content in the murine aorta.³⁶²

Other ABCA1 inducers

Sterane and sterane-like natural compounds

Several other agents were reported to induce ABCA1/Abca1 mRNA and/or ABCA1 protein level(s), with some studies reporting a unique mechanism of action for these agents. Such compounds include the sterane derivative ponasterone A (ecdysone; ABCA1 protein; ABCA1-mediated cholesterol and phospholipid transport),²⁰² and the enoxolone derivative glycyrrhizine (ABCA1 protein).⁴¹⁴ In addition, the sterane derivative and farnesoid-X-receptor (FXR) activator obeticholic acid induced Abca1 mRNA levels in vivo in the ileum of Srb1-deficient C57BL/6 mice.⁴¹⁵ In THP-1 macrophages, the sterane-like maslinic acid induced ABCA1 mRNA levels, paralleled with an increased cholesterol efflux from these cells.³⁹⁰ Finally, the Salvia miltiorrhiza-derived tanshindiol C was demonstrated to induce peroxiredoxin 1 mRNA (Prdx1) and protein (PRDX1) content in murine RAW264.7 cells.⁴¹⁶ Prdx1 was demonstrated to regulate Abca1 mRNA and ABCA1 protein expression. A reduction of intracellular cholesterol levels in murine peritoneal macrophages could also be observed.

Flavonoids

The flavonoids daidzein (Figure 2),³⁰⁹ kaempferol,³⁹⁷ and pratensein³⁰⁹ induced ABCA1 mRNA^309,397 and ABCA1 protein levels³⁰⁹ as well as ABCA1-mediated cholesterol efflux.³⁹⁷In addition, hesperetin-7-O-rutinosid (hesperidin) abrogated the negative effect of varenicline on ABCA1 protein expression in RAW264.7 macrophages.⁴¹⁷ The authors could underpin their findings with a reduction of aortic atherosclerotic plaques in Apoe knock-out C57BL/6 mice along with reduced lipid levels in peritoneal macrophages derived from these mice.

Polyphenols and polyphenol-like natural compounds

Several polyphenols and polyphenol-like compounds induced Abca1 mRNA^408,418 and ABCA1 protein^393,404 levels in murine^{393,404,408,418} and human³⁹³ macrophages, leading to an increased cholesterol efflux.^404,408,418 These include certain Cannabis sativa-derived stilbenoids⁴⁰⁴ as well as the Tadehagi triquetrum-derived phenylpropanoid glycosides urolithin A⁴¹⁸ and urolithin B (sulfate).³⁹³ In vivo, atherosclerotic plaques were reduced after urolothin B treatment. One phenylpropanoid glycoside was demonstrated to increase Lxra, but none of the other compounds could confirm these results. Given that the effect of all compounds on ABCA1 expression was similar, it is likely that another, yet unknown pathway was the major contributor to the observed effects.

Other natural compounds

Sodium butyrate induced Abca1 mRNA and ABCA1 protein levels in murine RAW264.7 cells, accompanied by an increased efflux of cholesterol from these cells.⁴¹⁹ This induction was reflected by increased ABCA1 protein content in vivo, reduced plasma cholesterol and triglyceride levels, and reduced aortic atherosclerotic lesions and hepatic steatosis in high fat diet-fed Apoe knock-out C57BL/6 mice.

Pharmacological drugs

Several pharmacological drugs induced ABCB1/Abca1 mRNA^309,420,421 and ABCA1 protein,^309,391,421 including the anti-obesity drug orlistat,³⁹¹ the antibiotic sulfoxaflor,⁴²⁰ the leukotriene receptor antagonist zafirlukast,⁴²¹ as well as the anthracyclines aclarubicin³⁰⁹ and pyrromycin.³⁰⁹ Zafirlukast in particular reduced intracellular cholesterol and lipid content in oxidized LDL-(oxLDL)-induced lipid-overloaded RAW264.7 macrophages, and increased cholesterol efflux from these cells.⁴²¹

Finally, it should be highlighted that mifepristone has frequently been used in a mifepristone-inducible transfection system to stabilize and increase ABCA1 expression in ABCA1-transfected baby hamster kidney (BHK)-21 cells. This ABCA1 induction could be functionally confirmed by increased ABCA1-mediated cholesterol and phospholipid efflux.^245,273,422

Synthetic compounds, HTS hits, and synthetic approaches

The purinergic P2Y7 receptor antagonists AZ-1, AZ-2, and AZ10606120 increased ABCA1 mRNA and ABCA1 protein levels and resulted in enhanced cholesterol efflux from human CCFSTTG1 astrocytoma cells.⁴²³ The polychlorinated biphenyl quinone 2,3,5-trichloro-6-phenyl-[1,4]-benzo-quinone (PCB29-pQ)⁴²⁴ and the fluorescigenic pyrazoline derivative 5 (FPD5)⁴²⁵ increased Abca1 mRNA⁴²⁴ and ABCA1 protein⁴²⁵ content in RAW264.7 macrophages and reduced cholesterol content in these cells.^424,425 In vivo, FPD5 reduced aortic lipid and cholesterol content and atherosclerotic lesions in Apoe knock-out C57BL/6 mice.

Inducers of other ABCA transporters

ABCA2 and ABCA3

As detailed above, ABCA2 and ABCA3 are believed to contribute to multidrug resistance in cancer.^{171,232-239,241,242} In human K562 leukemia cells, it was demonstrated that the tyrosine kinase inhibitor (TKI) imatinib induced increased levels of ABCA2 mRNA and ABCA2 protein.²³⁶ Furthermore, the TKIs dasatinib, imatinib, and nilotinib increased ABCA3 mRNA levels in various cancer cell lines as well as in TKI-treated leukemia patients.⁴²⁶ The antimetabolite 5-fluorouracil (5-FU) induced expression of ABCA3 mRNA in a cholangiocarcinoma cell line,⁴²⁷ and methotrexate increased ABCA2 and ABCA3 mRNA in a leukemia cell line.²⁴² Finally, the steroid hormone progesterone,¹⁷⁹ the antibiotic sulfoxaflor,⁴²⁰ and the endosomal cholesterol transport inhibitor U18666A¹⁷⁹ induced ABCA2/ Abca2 transcripts⁴²⁰ in Aphis gossypii⁴²⁰ as well as in ABCA2-transfected Chinese hamster ovary (CHO) cells and HepG2 cells¹⁷⁹

ABCA5 and ABCA6

As discussed earlier, cholesterol and its derivatives have been shown to induce ABCA1/Abca1 mRNA and/or ABCA1 protein levels.^{122,205,249,252,259,262-264,268,277,278,305-315,319-328} Induction by cholesterol has also been demonstrated for Abca5 mRNA and ABCA5 protein levels in RAW264.7 macrophages.³²¹ This effect relied on the induction of Lxra, Lxrb, and Pparg. Consequently, several LXR and PPAR agonists increased Abca5 expression, including bezafibrate (PPAR-α, PPAR-β, and PPAR-γ; Abca5 mRNA and ABCA5 protein), GW3965 (LXR; Abca5 mRNA), rosiglitazone (PPAR-γ; Abca5 mRNA), and troglitazone (PPAR-γ; Abca5 mRNA) in murine RAW264.7 macrophages.³²¹ In addition, the HMG-CoA-reductase inhibitor atorvastatin increased Abca5 mRNA and ABCA5 protein levels.³²¹ Interestingly, the ABCA1 inhibitor tacrolimus²⁴⁵ showed induction of ABCA5 mRNA in human brain microvascular endothelial cells.⁴²⁸

The HMG-CoA-reductase inhibitors lovastatin and mevastatin resulted in an induction of ABCA6 mRNA in the human endothelial cell line EA.hy926.⁴²⁹ Finally, in an Abca12 pig model of the rare and lethal skin disease Harlequin ichthyosis, it was demonstrated that treatment with the synthetic retinoid acitretin leads to a compensatory induction of Abca6 mRNA.⁴³⁰

ABCA7

Similarly to ABCA1,²⁰² the sterane derivative ponasterone A increased both ABCA7 protein expression and ABCA7-mediated transport, mainly of phospholipids, but also of cholesterol to a small extent.²⁰²

HMG-CoA-reductase inhibitors were described above to interfere with ABCA1/ Abca1^{312,318,330,343,362,411} and Abca5³²¹ expression. In addition, certain compounds were also demonstrated to interfere with Abca7 expression.^205,431 These include pravastatin^205,431 and rosuvastatin (Figure 2).⁴³¹ These agents increased Abca7 mRNA and ABCA7 protein levels in vitro,^205,431 whilst pravastatin had the same effects in vivo in murine peritoneal macrophages.⁴³¹ Surprisingly, this increase of Abca7 mRNA and ABCA7 protein levels was accompanied by a downregulation of Lxra and upregulation of Srebp2 in vitro.⁴³¹ Functionally, pravastatin and rosuvastatin reduced intracellular cholesterol content⁴³¹ and induced phagocytosis in vitro and in vivo.⁴³¹ These effects occurred in response to an ABCA1 downregulation by HMG-CoA-reductase inhibitors as described earlier.^{312,321,384,432,439,429} Due to their functional similarity, the upregulation of ABCA7 could be a compensatory mechanism to counteract the loss of ABCA1.¹⁹⁸ Similarly, the observed Lxra down- and Srebp up-regulation may be a compensatory mechanism to counteract the loss of intracellular cholesterol.

Finally, as described for ABCA1,⁴²² exposure of ABCA7-transfected BHK-21 cells to mifepristone increased ABCA7 protein content and ABCA7-mediated transport of phospholipids and, to a much lesser extent, of cholesterol.⁴²²

ABCA8

ABCA8 mRNA and ABCA8 protein content were induced by gemcitabine in PANC-1 and CFPAC-1 human pancreatic cancer cells.²²¹ In rat liver, an induction of Abca8 was demonstrated via microarray analysis of cDNA when the rats were exposed to polyethyleneglycol-block-polylactide nanoparticles.⁴³³

ABCA12

Several LXR and PPAR agonists induced ABCA12/Abca12 expression, such as 22-(R)-hydroxycholesterol (LXR),⁴³⁴ TO901317 (LXR),^430,434 ciglitazone (PPAR-γ),⁴³⁴ GI 251929X (PPAR-γ),⁴³⁴ troglitazone (PPAR-γ),⁴³⁴ ceramide N-hexanoyl-D-erythro-sphingosine (PPAR-δ),⁴³⁵ and GW610742 (PPAR-δ).⁴³⁴

Interestingly, inhibition of certain enzymes to prevent ceramide processing elevated intracellular ceramide content and subsequently ABCA12 mRNA levels.⁴³⁵ These enzymes include, for example, the glycosyl-ceramide-transferase synthase [_D threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-pro-panol (_D-PPMP), _D-threo-1-phenyl-2-palmitoyl-3-pyrrolidinopropanol (_D-PPPP / P4) and _DL-threo-1-phenyl-2-de-canoylamino-3-morpholino-1-propanol (_D-DDMP)], the sphingomyelin synthase [tricyclo[5.2.1.0^2,6]decanyl)ethanedithioic acid (D609 xanthate)], as well as the ceramidase [D-erythro-2-tetradecanoylamino-1-phenyl-1-propanol (_D-MAPP) and (_D NMAPPD / B13)].⁴³⁵

Downregulators

ABCA1

LXR and RXR pathways – intrinsic substrates

The intrinsic metabolite asymmetric dimethylarginine (ADMA) reduced Abca1 mRNA and ABCA1 protein levels in human and murine J744 macrophages in combination with oxLDL, resulting in increased intracellular cholesterol and triglyceride levels.³⁹² This was accompanied by decreased efflux of cholesterol from these cells. The authors suggested a negative effect on the LXR-α pathway. In this regard, the LXR-α downregulator homocysteine significantly reduced ABCA1/Abca1 mRNA and ABCA1 protein expression in vitro in THP-1 macrophages as well as in vivo in macrophages from Apoe knock-out C57BL/6 mice.³³⁵ The cattle metabolite dipeptide phenylalanine-proline decreased ABCA1 mRNA and ABCA1 protein levels in human colorectal adenocarcinoma-derived CaCo-2 cells.⁴³⁶ The observed downregulation of LXRB mRNA could explain the negative impact on ABCA1 expression. In vivo, the jejunal Abca1 mRNA levels were decreased in Wistar rats.⁴³⁶

The ABCA1 substrate α-tocopherol²³⁰ reduced ABCA1/Abca1 mRNA levels in vitro and in vivo.²³¹ The same effects were observed for γ-tocopherol in vitro, most likely through the same mechanism. The authors suggested a negative impact on the LXR pathway due to deprived oxycholesterol derivatives after α-tocopherol treatment both in vitro in Hep3B cells and in vivo in rat liver.²³¹

LXR and RXR pathways - sterane and sterane-like natural compounds

Cholesterol and its derivatives have extensively been used to induce ABCA1/Abca1 expression^{122,205,249,252,259,262-264,268,277,278,305-315,319-328} However, mid-term exposure to excess cholesterol decreased ABCA1 expression though a negative impact on Lxra, Lxrb, and Pparg expression.³²¹ Similar observations have been made for the sterol derivative dexamethasone, which also reduced ABCA1/Abca1 mRNA and ABCA1 protein expression in vitro and in vivo by downregulation of LXRA/Lxra mRNA and LXR-α protein levels as well as upregulation of Srebp2 and HMG-CoA-reductase gene expression (Hmgcr).⁴³⁷ Finally, an Abca1 mRNA reduction was observed in murine RAW264.7 macrophages for the Thelenota ananas-derived saponin desulfated holothurin A.⁴³⁸ Interestingly, Hmgcr was downregulated after exposure to desulfated holothurin A, which contradicts other findings.⁴³⁷

LXR and RXR pathways – other natural compounds

Certain chalcone derivatives also caused reduced expression of ABCA1 protein.³⁶³ In addition, lipopolysaccharides reduced ABCA1 protein content in endometrial endothelial cells from C57BL/6 mice, which was accompanied by increased cholesterol levels in these cells.³⁷⁴ A parallel reduction in LXR-α protein was also observed. Finally, the carcinogenic agent N-nitrosodiethylamine (NDEA) demonstrated in vivo in Wistar albino rats a downregulation of Lxra and Lxrb mRNA as well as LXR-α and LXR-β protein levels and, subsequently, ABCA1 protein.³⁶⁸

LXR and RXR pathways – synthetic compounds and HTS hits

In terms of other LXR antagonists and downregulators, GSK2033 (Figure 2),^272,330,333 5CPPSS-50,³⁵⁷ and SR9243³³³ reduced ABCA1 mRNA and ABCA1 protein expression.^{272,330,333,357}

HMG-CoA-reductase pathways – intrinsic substrates and pharmacological drugs

The peptide hormone angiotensin II reduced cholesterol efflux from murine peritoneal macrophages.⁴³⁹ This reduction could be reversed by the angiotensin II receptor antagonist losartan. The authors concluded that ABCA1 was not involved in this process, as no concurrent change in Abca1 expression was observed.⁴³⁹ However, in another report, angiotensin II indeed demonstrated a reduction of ABCA1 mRNA and ABCA1 protein levels in human podocytes.⁴⁴⁰ The authors concluded a contribution of the HMG-CoA-reductase, SREBP1, and SREBP2.⁴⁴⁰

Geranylgeraniol pyrophosphate (GGPP; Figure 2), a product of the mevalonate pathway, reduced ABCA1 mRNA expression in human macrophages, which was blocked by the prenylation inhibitors L836,978 and L-839,867.³¹⁴ In addition, a reduction of ABCA1-mediated cholesterol export was observed, which is also true for mevalonate itself.³¹⁸ GGPP was used as a standard ABCA1 downregulator in certain studies.^279,354,366

As discussed above, atorvastatin,³⁴³ fluvastatin,³¹² pitavastatin,^318,343 and simvasta-tin^312,343 have been shown to increase ABCA1/Abca1 mRNA levels,^312,343 and to enhance ABCA1-mediated cholesterol efflux.³¹⁸ However, atorvastatin,^312,321,384 fluvastatin,³¹² pitavastatin⁴³² and simvastatin^312,384 have also been reported to reduce ABCA1/Abca1 transcription^{312,321,384,432} and ABCA1-mediated cholesterol efflux.^384,431 These observations are in agreement with other reports on HMG-CoA-reductase inhibitors that downregulated ABCA1.^312,431 In particular, lovastatin,³¹² mevastatin (compactin),⁴¹² pravastatin,⁴³¹ and rosuvastatin^431,441 reduced ABCA1/Abca1 mRNA^312,431 and ABCA1 protein⁴³¹ levels. These findings are expected given that the loss of cholesterol by interruption of cholesterol synthesis leads to a compensatory reduction of cholesterol efflux.^314384,412 The contradictory results relating to ABCA1 may be caused by the use of variable experimental conditions between studies, such as different cell lines, assay methodologies, or small-molecule-related aspects, such as concentration, distribution, and protein binding.

Finally, a similar interconnection between HMG-CoA and ABCA1 was drawn for the antineoplastic agent mitotane, which downregulated ABCA1 mRNA⁴⁴¹ and increased intracellular cholesterol levels.^333,441 However, mitotane in combination with LXR antagonists and LXR downregulators had an inverse effect on mRNA regulation, increasing ABCA1 expression.³²⁷

PKC pathway - intrinsic substrates

Interestingly, it was also demonstrated that long-term exposure to low concentrations of 8-Br-cAMP, a standard ABCA1/Abca1 inducer,^{230,249,255,266,290,292} led to decreased APOE secretion from human monocyte-derived macrophages.²⁶⁶ APOE secretion can be considered as a surrogate marker for ABCA1-mediated cholesterol transport.

PPAR pathway – pharmacological drugs and synthetic compounds

Regarding the important PPAR pathway, it must be noted that troglitazone, indicated above as an ABCA1 inducer,²⁶⁸ was also reported to downregulate ABCA1 transcription.³²¹ These inconsistent effects may be explained partially by the different concentrations used (1 μM vs 10 μM),^268,321 but may also be related to cross-talk between the PPAR, LXR, and mevalonate pathways. The PPAR-γ antagonist GW9662 (Figure 2) reduced ABCA1 protein levels.⁴⁰⁶

Other ABCA1 downregulators – natural compounds

Other small-molecules have been reported to act as ABCA1/Abca1 downregulators, acting independently of the previously mentioned LXR, RXR, PPAR, and HMG-CoA-reductase pathways. Natural compounds such as α,β-unsaturated carbonyl derivative acrolein,⁴⁴² the polyphenol bisphenol A,⁴⁴³ and the polyphenol 1,2,3,4,6 penta-O-galloyl-β-_D-glucose⁴⁴⁴ demonstrated an Abca1 mRNA^443,444 and ABCA1 protein⁴⁴² downregulation in vitro^443,442 and in vivo.⁴⁴⁴ The effect of acrolein could be abrogated by 3-hydroxytyrosol,⁴⁴² an inducer of ABCA1 protein content.⁴⁴⁵

SREBP2 has been demonstrated to be targeted by EGCG in high fat diet-fed transgenic SREBP^+/+ Wistar rats, resulting in Abca1 mRNA downregulation, while an Abca1 mRNA upregulation could be observed under the same conditions in SREBP knock-out Wistar rats.⁴⁴⁶

Other ABCA1 downregulators – pharmacological drugs

Exposure of the human non-small cell lung cancer lines A549 and H358 to the antiepileptic drug valproate led to downregulation of ABCA1 mRNA and ABCA1 protein levels through a histone deacetylase 2-(HDAC2)-mediated mechanism. In parallel, the authors observed an increased sensitivity of these cells to cisplatin.⁴⁴⁷

The selective estrogen receptor modulators raloxifene, tamoxifen, and toremifene were reported to reduce ABCA1 protein content in THP-1 macrophages along with decreased cholesterol efflux and increased intracellular cholesterol levels.³⁴¹ Tamoxifen and raloxifene treatment decreased serum HDL-cholesterol levels in mice. In addition, tamoxifen reduced cholesterol levels in serum, liver, and feces of mice after injection with cholesterol-loaded macrophages.³⁴¹ Interestingly, the downregulation of ABCA1 protein content by these estrogen receptor modulators could not be demonstrated for murine liver, indicating a macrophage-specific effect.³⁴¹

Varenicline, a drug used in smoking cessation, was shown in vivo to promote aortic atherosclerotic lesions in Apoe knock-out C57BL/6 mice.^417,448 The authors demonstrated that intracellular lipid content in peritoneal macrophages was increased, and a decreased ABCA1 protein expression was confirmed in vitro in RAW264.7 macrophages. Finally, the antineoplastic agent gefitinib reduced ABCA1 protein content in various non-small cell lung cancer cell lines.⁴⁰⁰

Other ABCA1 downregulators – synthetic compounds

The plasticizer dibutyl phthalate³⁸⁹ and the PI3K/AKT inhibitor LY294002⁴²¹ reduced ABCA1 mRNA³⁸⁹ and ABCA1 protein^389,421 expression and increased cellular cholesterol and lipid levels³⁸⁹ in human³⁸⁹ and murine⁴²¹ macrophages.

The sphingosine kinase 1 and 2 inhibitor 4-{[4-(4-chlorophenyl)-2-thiazolyl]amino}phenol was demonstrated to downregulate ABCA1 protein expression in murine primary macrophages, which was dependent on the sphingosine kinase 2 as well as the sphingosine-1-phosphate receptor.³⁰⁶ This ABCA1 protein downregulation was accompanied by a reduced cholesterol efflux.

The acyl coenzyme A cholesteryl acyl transferase (ACAT) inhibitor ATR-101 reduced ABCA1 mRNA levels and induced an increase in intracellular cholesterol content in H295R cells.²⁵¹ The authors suggested that this was caused by inhibition of ABCA1 but provided no clear proof of direct inhibition of ABCA1. Therefore, this compound was classified as a downregulator.

Other ABCA transporters

ABCA2 and ABCA3

Compared to ABCA1, knowledge relating to downregulators of the other ABCA transporters is very limited. As discussed above, human leukemia cells exposed to imatinib displayed increased ABCA2 mRNA and ABCA2 protein expression.²³⁶ Celecoxib abrogated this effect.²³⁶ A similar observation was reported for ABCA3, where the anti-inflammatory drug indomethacin and the ABCA1 inhibitor sirolimus²⁴⁵ (Figure 2) downregulated ABCA3 mRNA in various cancer cell lines.^426,449,450 This treatment also resulted in a sensitization of these cell lines toward the TKIs dasatinib, imatinib, and nilotinib when treated with indomethacin.⁴²⁶

Other compounds were also reported to downregulate ABCA3/Abca3 including the flavonoid genistein,⁴⁵¹ lipopolysaccharides⁴⁵² – already demonstrated above as ABCA1 protein downregulators³⁷⁴ – and the translocator protein ligand PK11195.⁴⁵³ The effect of lipopolysaccharides could be abrogated by ascorbic acid (vitamin C).

ABCA5–ABCA9

Interestingly, the ABCA8 inhibitor²²² and ABCA1 protein inducer²⁵³ digoxin downregulated Abca5 and Abca7–9 in murine liver.⁴⁵⁴ The HMG-CoA-reductase inhibitors lovastatin and mevastatin downregulated ABCA6 mRNA in human umbilical vein endothelial cells.⁴²⁹ The cholesterol derivative 25-hydroxycholesterol, which was introduced above as an ABCA1 mRNA inducer,³²⁷ showed the opposite effect on ABCA7 mRNA.³²⁴ This finding is in agreement with a report stating that excess cholesterol reduced ABCA7 protein content in both human and murine fibroblasts.²⁰⁵

Stabilizers of ABCA transporters

Stabilizers are compounds that promote functional activity of ABC transporters through increasing their presence at the site of action (e.g., the cell membrane) either without interfering with mRNA or protein levels, or in addition to these effects. The categorization is difficult, as the necessary information regarding many modulators of ABCA transporters is lacking and the underlying mode of modulation cannot be precisely identified. In this section, we consider only those modulators which predominantly interfere with ABCA1 trafficking, with relatively minor or no additional modes of action/modulation. Stabilizers are of particular interest, as they may represent a novel generation of functional ABC transporter activators, expanding treatment options for several diseases, particularly AD.

ABCA1

Probucol and cyclosporine A were demonstrated above to decrease ABCA1 turnover and increasing ABCA1 protein content at the cell membrane.^246,275 Arakawa et al. demonstrated that the probucol metabolites spiroquinone and diphenoquinone did not inhibit ABCA1-mediated transport like their parent compound but rather increased the fraction of functional ABCA1 in the cell membrane.²⁷⁵ This stabilization led to increased cholesterol and phospholipid efflux. Both effects were observed at very low nanomolar concentrations,²⁷⁵ while Abca1 mRNA remained stable.²⁷⁵ Strikingly, spiroquinone and diphenoquinone decreased vascular lipid deposits in vivo in cholesterol-fed rabbits,²⁷⁵ which may be of relevance for AD and potentially other neurodegenerative diseases.

A similar mode of stabilization, albeit with less potency and no in vivo confirmation, has been observed for the flavonoid wogonin,²⁵⁴ the olive oil-derived compound erythrodiol,³⁹⁵ and certain thiol proteinase inhibitors, in particular N-acetyl-Leu-Leu-norleucinal and leupeptin.^316,386 Finally, the ABCA1 mRNA and ABCA1 protein inducer testosterone was demonstrated to promote ABCA1 trafficking to the cell membrane.³⁵⁷

Other ABCA transporters

The cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7) correctors C13,⁴⁵⁵ C14,⁴⁵⁵ C17,⁴⁵⁵ genistein,⁴⁵⁶ and ivacaftor (Figure 2)⁴⁵⁶ were demonstrated to rescue ABCA3 mutants by increasing total ABCA3 mutant protein levels,⁴⁵⁵ promoting subcellular targeting of ABCA3 into vesicular bodies,⁴⁵⁵ and improving lipid transport function of ABCA3.⁴⁵⁶ Furthermore, the correctors lumacaftor (VX-809; Figure 2), C3, and C4, and C18 increased the presence of ABCA4 at the cell membrane in ABCA4-overexpressing HEK293 cells, indicating promotion of ABCA4 trafficking to the plasma membrane.^457,458 Promotion of trafficking has already been demonstrated for other ABC transporters, such as ABCC1^23,24 and ABCC7.⁴⁵⁹ Hence, this mechanism represents a new potential therapeutic option for ABCA transporter-related AD. As proposed for ABCC7,⁴⁶⁰ the authors suggested a direct binding of the correctors to the ABCA4 protein,⁴⁵⁷ which has not yet been proven.

In an Abca12 pig model of Harlequin ichthyosis, acitretin (Figure 2) treatment resulted in a redistribution of ABCA12 in the skin compared to wild-type pigs, and thus, a higher survival rate.⁴³⁰

Destabilizers of ABCA transporters

Natural compounds

In contrast to compounds that promote trafficking of functional ABCA1 to the plasma membrane, other compounds that have the opposite effect have been named ‘destablizers’. So far, only agents targeting ABCA1 are known. The lactone antibiotic brefeldin A (Figure 2) interfered with ABCA1 cell-surface localization, recycling, and intracellular trafficking.^387,461-463 These effects were at least in part dependent on the interaction with brefeldin 1-inhibited guanine nucleotide exchange protein (BIG1).⁴⁶¹ This interference reduced the functional fraction of ABCA1 and, consequently, ABCA1-mediated cholesterol and phospholipid transport.²⁵⁵ Similar observations have been made for the polyether-antibiotics monensin, which reduced ABCA1 turnover and trapped it inside endo- and lysosomes. Subsequently, monensin reduced the functional presence of ABCA1 at the cell surface,⁴⁶⁴ lowered cholesterol efflux,⁴⁶³ and increased intracellular cholesterol content.^463,464 The same was demonstrated for nigericin, another polyether-antibiotic, which increased intracellular cholesterol concentration,⁴⁶³ and inhibited ABCA1-mediated cholesterol efflux from RAW264.7 macrophages.³⁸⁵ Inhibition of intracellular organelle transport as suggested for brefeldin A^387,461-463 and monensin^463,464 likely applies to nigericin as well.^463,465 In addition, the endoplasmic reticulum stress promotor, tunicamycin, also reduced ABCA1 protein levels.^360,466 This ‘downregulation’ is most likely mediated though stress-induced impaired ABCA1 trafficking and/or increased ABCA1 degradation.⁴⁶⁶ However, in terms of selective targeting of ABCA1 in particular, or ABCA transporters in general, these agents are less suitable as in vivo agents and serve better as in vitro controls.

The palmitic acid derivative 2-bromopalmitate (Figure 2) inhibited trafficking of ABCA1 to the plasma membrane and reduced ABCA1-mediated cholesterol efflux.^273,467 However, the observed effect that ABCA1 did not translocate to the cell membrane in HEK293/ABCA1 cells⁴⁶⁷ has not been demonstrated in BHK-21/ABCA1 cells.²⁷³

Pharmacological drugs

Interestingly, the experimental anticancer drug serdemetan (JNJ-26854165) was demonstrated to induce Abca1 mRNA levels but reduce ABCA1-mediated cholesterol efflux.⁴⁶⁸ The Abca1 mRNA induction was due to induction of Lxra and Lxrb. The Abca1 mRNA increase was also reflected at the protein level, which increased within 48 hours of exposure to serdemetan before a sudden decrease occurred. The authors also showed that ABCA1 turnover and degradation were increased. Thus, serdemetan can be considered a destabilizer.

Synthetic compounds

Cycloheximide was frequently used to interrupt intracellular trafficking of vesicles, including ABCA1 containing endo- and lysosomes.^387,464,468

As mentioned earlier, ABCA1 is stabilized by N-acetyl-Leu-Leu-norleucinal.^316,386 This stabilization could be abrogated by the protein kinase C inhibitor Gö6976, which affected not only ABCA1 protein content, but also cholesterol and phospholipid transport.³⁸⁶

PART II: PIPELINE DEVELOPMENT TO GAIN NOVEL DIAGNOSTICS AND THERAPEUTICS

In silico methodologies to predict novel lead structures

Rational drug design is the innovative process of identifying pharmaceutically relevant drug candidates. It is based on the information obtained in association with the drug target, e.g., ABC transporters. In the following section, we will discuss computational approaches for in silico operations that help to identify novel lead molecules for potential diagnostic and therapeutic application.

Structure-based drug design

The development of computational methodologies for structure-based drug design to understand the relationship between transporter sequence/structure and function depends on the availability of structural as well as biological information. Recent advances in experimental approaches for structure determination have facilitated high-quality depictions of the structures of a growing number of ABC transporters in different conformational states.⁴⁶⁹ These experimental approaches include in particular X-ray crystallography and cryo-electron microscopy (cryo-EM).

Recently, the cryo-EM structures of human ABCA1⁴⁷⁰ and human ABCA4^471-473 with resolutions of 4.1 Å and 3.3–3.6 Å, respectively, were reported. In addition, a cryo-EM structure of human ABCA7 has been announced⁴⁷⁴ on bioRxiv (biorxiv.org), which was, however, not published to this date (PDB ID: 7KQC). Nevertheless, a homology model of ABCA7 has been recently developed.⁴⁷⁵ Figure 4 shows the structures of ABCA1, ABCA4, and ABCA7 as determined by cryo-EM as well as homology modelling.

Considering the available structural knowledge, a ‘common’ ABCA transporter possesses a very long amino acid sequence (>2000 amino acids) and consists of two membrane-spanning domains (MSD1 and MSD2) each composed of six transmembrane helices (TM1–6 and TM7–12). These MSDs are followed by a cytoplasmic region comprising a nucleotide-binding domain (NBD1 and NBD2) and a small regulatory (R1 and R2) domain, which have been proposed to stabilize the interaction between NBD1 and NBD2^470,473 and were found to strongly interact with each another in the absence of ATP.^471,472

ABCA transporters are ‘type II transporters’ in which the MSDs indeed form a tunnel for substrate translocation from the cytosol to the lumen, however, represent separate entities without swapping/twisting of the MSDs, as this is the case with classical ‘type I transporters’ like ABCB1.⁴⁷⁶ Most TMs are completely exposed to the hydrophobic environment of the membrane, which could promote the attraction and binding of fat-soluble cholesterol as well as phospholipids before guidance to and through the substrate translocation tunnel, and which hosts several cholesterol and phospholipid binding sites.^470-474

A unique feature amongst ABCA transporters in comparison to other ABC transporters is the existence of two large extracellular domains (ECD1 and ECD2). These domains together form a channel embedded in hydrophobic amino acids^470-472 and are believed to facilitate intermediate storage of cholesterol⁴⁷⁰ and phospholipids. They have also been suggested as the primary binding site of APOA1,^471,477 as indicated by the latest data on ABCA4.⁴⁷¹ A large gap exists between the ECDs and MSDs, pointing to strong conformational changes that are required for ABCA transporter function.⁴⁷⁰ Another common feature amongst ABCA transporters are four intracellular and extracellular helices (IH1–4 and EH1–4), which are believed to provide the necessary flexibility for interaction between the MSDs and NBDs in the substrate translocation process,⁴⁷⁸ and were suggested to enable proper folding and function of these transporters.⁴⁷¹

Of important note is that ABCA1 and ABCA4 share sequential and structural similarities with the ABCG family, in particular with ABCG5/ABCG8,⁴⁷⁰ which is the model type II transporter.⁴⁷⁸ This similarity suggests an evolutionary relevance amongst various ABC transporter subfamilies. More importantly, conserved sequential and structural similarities also support the translation of knowledge gained on other ABC transporter subfamilies to ABCA transporters.^470,472 This is of particular interest when novel lead structures for new pharmacological targets, in this case under-studied ABC transporters,¹⁸ are focused,^6,18 and specific binding sites located within the MSDs or NBDs are targeted.

Based on the sequence information of ABC transporters within the same family, homology-modeling techniques are the preferred choice for structure determination and binding site elucidation if these subtypes do not yield X-ray or cryo-EM structures. This methodology is of particular relevance for closely related homologs with high medical relevance,¹⁹⁸ such as ABCA7 (similarity A1/A7: 54%; similarity A4/A7: 49%).²⁰⁰ The generated homology models can be refined further by molecular dynamics simulation, in which the transporter movement (‘trajectory’) is simulated to potentially unravel relevant transporter conformations. Very recently, potential ABCA1 drug binding sites have been proposed by this methodology,⁴⁷⁹ and an ABCA7 homology model has been developed for molecular docking experiments.⁴⁷⁵

Molecular docking is a very popular method for predicting binding orientations or poses of small-molecules within the transporter. Most often, the docking programs account for full conformational flexibility of ligands within the binding site, treating the protein as a rigid body. Binding site identification is an important prerequisite in the structure-based drug design implementation. In terms of ABC transporters, the search for binding hot spots and cavities on the entire volume of the protein (e.g., through blind docking) is necessary due to the general lack of information on binding sites of ABC transporters.

Recently, in search of highly effective modulators addressing ABCG2-mediated MDR, derivatives of quinazolines were synthesized and biologically assessed using a Hoechst 33342 accumulation assay.⁴⁸⁰ By utilizing the cryo-EM structure of ABCG2,⁴⁸¹ molecular docking studies were performed using a fragment-based approach.⁴⁸² This approach was used to gain insights into the molecular determinants involved in the formation of the transporter-substrate complex.⁴⁸⁰ Based on the docking studies, the putative binding site of the ABCG2 substrate, Hoechst 33342, and its interaction with the amino acids in the binding pocket was proposed.⁴⁸⁰ The predicted binding pose was rationalized based on the mutagenesis data reported in the literature^483-487 and further confirmed with kinetic studies to determine the mode of inhibition.⁴⁸⁰ This subsequent structure-based approach led to the discovery of highly potent pyrimidine-based ABCG2 inhibitors,^488,489 specifically by identifying a novel binding pocket of this transporter.⁴⁸⁸ In terms of ABCA transporters, molecular docking experiments with the newly derived ABCA7 homology model applying a set of diverse pan-ABC transporter inhibitors revealed a putative common ‘multitarget binding site’ identified within the transmembrane domains of ABCA7. It must be noted that the nucleotide binding domains are the most highly conserved regions amongst all ABC transporters, and hence, may also represent a(nother) multitarget binding site for certain drugs. However, the vast majority of data reported in the past hint to the transmembrane domains as the actual venue of bioactivity in terms of ABC transporter modulation.⁴⁷²

These results as described above^{475,480,488,489} give this methodology a high relevance in the drug development process in terms of novel lead molecules in general, and provide the basis for rationally designed structure-guided approaches for the identification of modulators of ABCA transporters in particular, as recently demonstrated for ABCA7.⁴⁷⁵

Ligand-based drug design

Similarity search

The analysis of structure-activity relationships using ligand-based approaches is an essential component of medicinal chemistry and pharmacology of ABC transporters. This becomes evident as X-ray or cryo-EM structures of most ABC transporter subtypes are lacking to serve as suitable templates with sufficient similarity for generating homology models. Ligand-based approaches establish a correlation between the molecular structure of a small-molecule and the triggered biological response of the target. The chemical representation of the molecules is often expressed using descriptors, which are attributes that conserve the physicochemical information of the molecule. These descriptors refer to generic properties such as LogP, molecular weight, polar surface area, rotatable bonds, or molar refractivity. Alternatively, structural representations of the molecules can form fingerprints that portray existent molecular features of the molecule in a binary code. These fingerprints are, for example, path-like,⁴⁹⁰ or circular-based,^491,492 such as MACCS or ECFP4, respectively. Utilizing these representations of molecules, similarity-driven virtual screenings can be applied. Here, molecules are extracted from a virtual library of millions or billions of compounds compared to the bioactive template molecule(s) according to the similarity principle. The abstract representation of molecules enables clustering of compounds, which is a methodology to categorize a diverse set of molecules. Moreover, these abstract representations can be used in different machine learning (artificial intelligence) approaches.

Pharmacophore modelling

Another common approach is pharmacophore modelling, which analyzes a number of ligands with a common mechanism of action. The model is the ensemble of common chemical features that are required to ensure the molecular interaction of the ligands with the target, such as hydrogen bond donors and acceptors as well as aromatic and hydrophobic centers. The pharmacophore models are generated by extracting common molecular features through flexible alignment of the active biomolecules.^493,494 This can be achieved by generating all possible conformations of the ligand and aligning them to determine the essential chemical features and molecular orientation to construct the pharmacophore model. The conformational flexibility of the ligands representing the chemical features is the key factor in the pharmacophore model generation.

Pattern analysis

In addition to these classical computational approaches, similarity search and pharmacophore modelling, a pattern analysis approach (‘C@PA’ = computer-aided pattern analysis’) has been reported recently.^18,19,495 Pattern analysis extracts both basic scaffolds and the statistical distribution of substructural elements amongst the template ligands. It works similarly to non-physicochemical properties-related fingerprints and conserves substructural features as they are present in the molecules. Pattern analysis has specifically been derived for the development of novel potent multitarget ABC transporter inhibitors. The basic operations were the categorization of bioactive molecules according to their inhibitory power against specific ABC transporters and their classification according to their selectivity profile. The respective classes can statistically be analyzed for both their basic scaffolds and/or their substructural composition to extract the desired pharmacological profile and target preferences. The generated model focused multitargeting of ABC transporters, and resulted in a biological hit rate of 21.7%.¹⁹ Adaption of the model (‘C@PA_1.2’) through additional non-statistical and exploratory measures increased the biological hit rate to 40%,¹⁸ and an additional extension of the model enabled the discovery of the ‘outer multitarget modulator landscape’, which represented weak multitarget bioactivities (>10 μM) supporting the discovery of a larger number of multitarget agents.⁴⁹⁵ The hit rates are impressive considering that this approach takes several targets with individual ‘ligand preferences’ into account. Furthermore, as several ABC transporters of distinct subfamilies were considered (ABCB1, ABCC1, ABCG2), the resultant multitarget agents open up the possibility to explore under-studied ABC transporters,¹⁸ in particular ABCA transporters in terms of AD.^6,14

Combined approaches

Apart from the individual use of these methodologies, combined approaches may lead to improved hit rates and better prediction capabilities with respect to bioactivity of small-molecules. This has in particular been demonstrated for a combined virtual screening approach using similarity search and pharmacophore modelling for the discovery of novel ABCC1 inhibitors.⁴⁹³ Also, certain pattern analysis approaches have used a data set derived from a similarity search and pharmacophore modelling approach, and hence, can also be considered a combined computational approach.^18,495

In vitro methodologies to assess novel lead structures

The previous sections have already outlined the diverse testing systems that have been used to assess the modulatory effects of effectors toward ABCA transporters. The following section will highlight the ABCA transporter-expressing host systems and the related assays that can be implemented into the pipeline for the assessment of novel lead molecules as potential ABCA transporter diagnostics or therapeutics.

Host system of ABCA transporters

The transporter host system (ABCA transporter carrying unit) can be categorized into (i) living-cell-based or (ii) membrane preparation-/vesicle-based (including isolated and reconstituted proteins). The vast majority of biological investigations used living cells. Here, two different living cell-based transporter host systems can be differentiated: (i) native/induced/selected cells and (ii) transfected cells.

Native ABCA transporters-expressing living cells

Native/induced/selected cells naturally express the respective ABCA transporter or have been exposed to a ‘standard’ inducer, for example, the ABCA1 inducers 22-(R)-hydroxycholesterol,^{122,205,249,252,259,262-264,268,277,278,305-315} TO901317,^{205,245,250,252,259,260,262,264,271,272,279,
280,282,308,310,317,319,322,324,326,328-345} or 8-Br cAMP,^{230,249,255,266,290,292} and overexpress the respective transporter in response (e.g., ABCA1). Most commonly, human or murine cells have been used. Table 4 summarizes the cell lines used to assess the ABCA transporter modulators discussed in the previous sections. It must be noted that the addressed pathways regulate also the overexpression of other ABC transporters. In terms of the studies of ABCA1, the co-expression (i.e., co-upregulation and co-downregulation) of other members, such as ABCG1, has frequently been observed.^{160,320,335,364,366,402,410,418,421,448}

Table 4. Non-exhaustive list of native ABCA transporters-expressing cell lines that have been established in the assessment of small-molecule modulators of ABCA transporters.

In terms of ABCA1, most studies have been conducted with human THP1,^{231,245,249,256,268,272,275,292,308,310,312-316,321,328,335,338,339,341,342,360,363,364,366,377,384,388-397} murine J774.A1,^{252,254,255,259,265,271,278,289-292,384,392,393} or murine RAW264.7 macrophages. ^{230,249,312,313,321,336,339,
342,352,360,365,367,369,375,376,381,385,399,402,404,406,408,410,416-419,421,424,425,438,442,448} In the set-up of a drug development pipeline, these cell lines are the backbone of the in vitro assessment of potential candidates.

Regarding other ABCA transporters, the situation is much more complicated due to the lack of cell lines that naturally (and almost exclusively) express the respective ABCA transporter. Consequently, these ABCA transporters are much less studied and well-established. However, transfected cell lines are of great help to study one particular transporter instead of using native cell lines that may co-express several members.

ABCA transporters-transfected living cells

In terms of ABCA1, cell lines transfected with human ABCA1 have often been used, e.g., human embryonic kidney (HEK) cells (HEK293/ABCA1)^{171,201,202,249,260,267,270,275,329,352,386,464,467,498,499} and baby hamster kidney (BHK) cells (BHK-21/ABCA1).^{230,245,273,292,422} These transporter host systems have also been used to study other transporters, ABCA2,^498,500 ABCA3,^235,241,498 ABCA4,^{133-136,201,457,458,501,502} ABCA5,⁵⁰³ ABCA7,^{201,202,386,422,498} ABCA8,¹⁰ ABCA12,⁴⁹⁸ and ABCA13.⁴⁸

Transfected cells often express lower levels of the introduced transporter than native cell lines, which is a problem if the host cell lines (e.g., HEK or BHK-21) naturally express other ABC transporters as well. However, these transporter host systems are suitable to confirm results, and might be the only possibility to address ABCA transporters other than ABCA1.

Isolated ABCA transport proteins

Finally, apart from intact cells, vesicles of enriched or purified/reconstituted ABCA transporters have also been used to assess transporter function. Compared with living-cell based assays, this kind of host system is rarely represented in the literature regarding ABCA transporters.^{133-139,201,499-502,504-506} Specifically ATPase assays are popular to assess functional ABC transporter modulation.^{23,24,507-510} While transport protein purification and reconstitution in vesicles or nano discs requires advanced engineering, and is expensive and resource-consuming, membrane preparations of transporters, in particular for ATPase assays, are much more feasible. However, this method has been used somewhat scarcely for ABCA transporter function assessment.^{133-135,137-139,201,499-502,504-506}

Functional assessment of ABCA transporters

Two groups of tracers have been established in terms of ABCA transporter function: (i) radiolabeled substrates,^{250,272,305,306,338,339,354,364,366,393,395,404,419,511,512,136,222,230,245,249,253,255,259,260,262,264,265,267-270,
273,276,278,289-292,311,313,315,318,329,341,367,377,381,384,385,464,467,499,513} and (ii) fluorescent substrates.^{171,201,238,
251,252,254,256,258,261,271,282,308,319,321,330,332,335,342,360,379,389,390,392,397,402,406,455,456,468,514-518} 

Radiolabeled tracers of ABCA transport function

In terms of radiolabeled substrates, cholesterol is by far the most frequently used genuineABCA1 substrate,^{230,245,249,255,260,264,265,267-270,272,273,276,278,289-292,305,306,313,315,318,329,338,339,354,366,367,381,384,385,
393-395,404,408,419,464,467,499,512} followed by phospholipid(-components).^{249,255,267,269,273,311,464,467,514} However, other substrates have also been used. These substrates include mostly molecules with sterane scaffold, such as β-sitosterol (ABCA1)²⁶² and estradiol-β-glucuronide (ABCA8).²²² Moreover, lipid-like substrates have attracted attention, like sphingosine-1-phosphate (ABCA1),^229,496 α-tocopherol (ABCA1),²³⁰ and ATRA (ABCA4).¹³⁶ Notably, radiolabeled substrates are very effective in terms of accurate tracing of protein function, as these molecules are not changed in their molecular integrity in contrast to fluorescence probes.^{171,201,238,251,252,254,256,258,261,271,282,308,319,321,330,332,335,342,360,379,389,390,392,397,402,406,455,456,468,
514-518} On the downside, conducting these experiments is constrained to regulatory requirements and requires extensive staff training as well as expensive safety measures and laboratory equipment.

Fluorescent tracers of ABCA transport function

Regarding fluorescent derivatives of cholesterol and phospholipids, two major types can be differentiated: (i) 7-nitro-2,1,3-benzooxadiazole (NBD) derivatives^{201,251,252,254,256,258,261,308,335,342,360,379,389,390,392,394,397,402,
406,408,468} and (ii) 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) derivatives.^{271,282,319,321,330,332,455,456,
515-517} Other fluorophore-labeled dyes have been reported, too, including the sterane analog dansyl-estramustine,^171,238,518 and propargyl choline, which is processed in vitro into propargylated phospholipids.⁵¹⁴

In addition to the stated fluorescent tracers of ABCA transport function, several other derivatives of other substrates can be proposed. For example, N-3-oxododecanoyl-L-homoserine lactone (3OC12-HSL) was suggested as ABCA1 substrate, but final proof was missing.⁵¹⁹ Thus, it may be a suitable candidate for validation in a new set-up in vitro assay for ABCA1 (and potentially other ABCA transporters). Other examples of potential probes are fluorescenct dyes that stand in association with cellular cholesterol and phospholipid distribution and ABCA1-mediated cholesterol and phospholipid transport.⁵¹⁶ These include, for example, β BODIPY FL C5-HPC, β-BODIPY FL C12-HPC, BODIPY TR ceramide, and Red/Green BODIPY PC-A2, amongst many others.^520-522

Fluorescenct dyes are well-established tracers of ABC transporter function,^{18,19,23,24,284,480,488,489,493,507,
523-525} and the knowledge that has accumulated regarding the well-studied ABC transporters ABCB1, ABCC1, and ABCG2 can be transferred to ABCA transporters as well. However, the added fluorophore changes the molecular composition of the tracing molecules. This alteration inheres the potential risk of changing affinities and even the binding site(s) of these molecules, undermining functional-kinetic analyses regarding binding site determination and elucidation of the mode of action. Nevertheless, fluorescence probes are – if used and established correctly – extremely reliable, and can be used without regulatory restrictions and necessity of special equipment, except for microplate readers and/or flow cytometers.

Colorimetric determination of ABCA transport function – ATPase assays

As mentioned above, ATPase assays have also been used to functionally analyze ABCA transporter function, in particular for ABCA1,^{201,499,505,506} ABCA2,⁵⁰⁰ ABCA3^139,504 ABCA4,^{133-135,137,138,201,501,502} and ABCA7,²⁰¹ although this methodology has been used somewhat rarely compared to other functional approaches. ATPase assays are based on the principle that the active transport of any substrate of ABC transporters consumes energy. This energy is derived from the cleavage of ATP to ADP and P_i, and can be detected by different methodologies.^{23,24,507-510,526} Table 5 highlights known ATPase modulators of ABCA transporters and the associated literature reports.

Table 5. Summary of known ATPase modulators of ABCA transporters.

^a u.c. = unspecified concentration

ATPase assays have been and still are popular in terms of functional ABC transporter modulation in general.^{23,24,507-510} Strikingly, the NBDs of ABC transporters are – in contrast to the various binding sites identified within the transmembrane domains of ABC transporters⁴⁷⁵ – highly conserved. This conservation enables targeting of ABCA NBDs by known ATPase modulators of other ABC transporters. Therefore, ABCA transporter function can be detected by methodologies that have already been established for other ABC transporters.^{23,24,507-510,526} This transfer of knowledge will be of great use to confirm obtained results from other functional ABCA transporter analyses.

Colorimetric determination of ABCA transport function – other detection methodologies

As a final note, it must be mentioned that other colorimetric analyses were also used to quantify the ABCA transporter-mediated function, specifically for transport of cholesterol or choline-containing lipids, using commercially available assay kits.^{202,205,246,251,268,272,275,329-332,334,336,354,365,366,369,372,374-376,386-389,392,405,
406,416,418,421,422,424,425,441,511} However, these methodologies require time-consuming extraction processes of the lipids, and hence, are less suitable to track the function of ABCA transporters in real-time and to determine kinetic aspects of their cholesterol and lipid transport.

In rare instances, the extraction of lipid components was accomplished after incubation with a radioactive marker.²⁴⁶ While this is a valid methodology to accurately determine lipid components within cells, it increases workload and attracts regulatory constraints.

Gas-liquid chromatography has also been used in some reports.^353,355 An extraction-free staining of cholesterol inside of cells was also demonstrated (filipin III^{251,331,333,341,358} or Oil Red O staining ^{330,332,364,366,369,375,388,389,392,393,399,402,410,417,421,425,448}).

However, these systems are not suitable to track single-cell ABCA-mediated cholesterol or phospholipid transport.

Quantification of ABCA transporter regulation

Besides qPCR and western blotting, ABCA transporter expression was reported in several studies using fluorimetric assays. This was accomplished with either (i) green fluorescent protein-(GFP)- tagged/labelled ABCA transporters^{235,241,261,275,386,422,464,504} or (ii) luciferase promotor-(LUC)-transfected^{271,309,319,352,367,379,381,405,
406,419,436,447} ABCA transporter cells in luciferase reporter gene assays.

In vivo assessment of clinical candidates

In vivo models play a key role in drug discovery. Although in vitro and cellular models are less expensive and less time consuming, in vivo models are needed to test ABCA modulators under physiological conditions. Safety, toxicity, and efficacy of a drug candidate must be tested in an in vivo model as a last step before transferring it to clinical evaluation. However, these models also have disadvantages. Animal studies are time consuming and require advanced personnel training and resources for maintaining the animals. In addition, although they are closer to humans than in vitro models, there are considerable physiological differences between species with respect to drug absorption, metabolism, and excretion, which may impede translatability. Furthermore, the use of animals in research has its ethical concerns. Thus, in recent years, research has been directed to reduce animal use and increase animal welfare.

In vivo models have previously been used to study the role of ABCA transporters in physiology and disease as described above. Thus, there are already available animal models for testing of ABCA modulators for the most prominent subtypes (Table 6). As stated above, these models represent the last step before clinical evaluation of potential small-molecule therapeutics in humans. Thus, after in silico identification and in vitro assessment, these in vivo models are the third column in the development of novel ABCA transporter diagnostics and therapeutics. In the following section, different in vivo models will be described in more detail.

Table 6. Animal models to study the functional and pathological role of ABCA transporters.

Knock-out mouse models

A genetic knock-out mouse model is an animal model in which one or more genes of interest have been deactivated or removed by means of gene targeting. Knock-out animals allow for direct investigation of the effect of a specific gene in an organism, as the loss of gene activity often causes phenotypic changes uncovering the function and biological mechanism of the targeted gene.⁵³⁵ Knock-out mice have become one of the most useful scientific tools to analyze the human genome and its potential roles in many diseases.⁵³⁵ Thus, knock-out animals are currently essential experimental tools for the investigation of genetic disorders and the evaluation of novel drugs.⁵³⁶ Furthermore, the current knowledge on genome editing using the CRISPR/Cas9 system makes generation of knock-out lines considerably faster than with the use of embryonic stem cells. To no surprise, this method has quickly become the most powerful tool for generating genetic models.⁵³⁷

Knock-out animal models are designed with two variables in mind: (i) where and (ii) when is the gene of interest deactivated. The simplest and most common approach is a constitutive, ubiquitous knock-out, i.e., the product protein is absent permanently in all cells of an organism. To overcome limitations of this broad approach, more refined models have been developed. These conditional models use Cre-Lox recombination to target a gene either in specific cell populations, at specific time points, or a combination of both. Here, the target gene is modified by inserting two loxP sites. The flanked gene segment can then be excised by the Cre recombinase. Cre activity, i.e., gene knock-out, can be limited to certain cell populations by appropriate promotor choice and/or linked to a tamoxifen-responsive element to control the exact time point at which the knock-out is induced.

Until now, several Abca animal knock-out models have been described, which are summarized in Table 6. These models are mainly mouse lines, except for ABCA13 (monkey).⁵³⁴ These animal models have contributed fundamentally to identifying the role of ABCA transporters in physiological conditions as well as in disease pathogenesis. In addition, these models can be used for novel drug testing, as they provide information about target specificity. If a drug is 100% specific for a transporter, knock-out of this transporter should completely abolish the drug’s effects observed in naïve animals. However, gene knock-outs often have phenotypical effects per se that need to be taken into account when evaluating drug effects.

RNAi models

The use of RNA interference (RNAi) is an alternative to knock-out models. This technique is based on post-transcriptional silencing of the targeted gene using siRNA molecules that are designed to bind to the target mRNA.⁵³⁸ This process will deactivate the mRNA using the cell’s own defense mechanism against pathogens. In contrast to standard knock-out models, this silencing is temporary as the siRNA molecule will be degraded but the gene transcription continues.⁵²⁷

To avoid this temporal limitation, short-hairpin RNA (shRNA) has been developed. This method is based on the use of vectors that incorporate into the cell DNA and encode for shRNA. After transcription, these vectors are processed into siRNA. These shRNAs are continuously transcribed, increasing reproducibility of results.⁵³⁹

Overexpression models

Similar to knock-out models, overexpression models can be used to investigate the function of a gene by evaluating the resultant phenotype. In addition, overexpression models have long been used for modeling diseases such as AD⁵⁴⁰ or PD.⁵⁴¹

In the investigation of ABCA transporters, these models can resemble the effect of chronic activation of the transporters and may help to identify its physiological functions by evaluating the pathways upregulated in comparison to control animals.¹²⁷

Humanized ABC transporter mouse models

Before it can be translated into clinical practice, each novel drug candidate must be tested in an in vivo model. However, the translational value of the animal model largely depends on whether the disease pathway under investigation is conserved between the two species. Therefore, replacing the original (e.g., murine) gene by the respective human gene likely improves the animal model, and thus, is beneficial for evaluating a novel drug’s efficacy and specificity in clinical practice.⁵⁴² With this approach, mice can be used as tools for pre-clinical screening and efficacy evaluation of new drugs, given their improved ability to predict human responses to treatments.

Our group has previously established a humanized ABCC1 mouse model,⁵⁴³ and an ABCA7 model is under characterization. Here, we generated knock-in mouse models producing a chimeric protein that is completely human except for one amino acid.⁵⁴³ In addition, as this gene was flanked by loxP sites, this humanized model can be knocked out in specific cell populations and at a specific age.⁵⁴³ Models such as these represent the future of pre-clinical drug candidate evaluation.

In addition, Dallas et al. successfully generated a humanized ABCG2 mouse model.⁵⁴⁴ However, other models, such as humanized ABCB1 mice, were not successful despite multiple attempts.⁵⁴⁵

Disease models

In addition, all the models described above can also be used to study the role of a gene for the pathophysiology of specific diseases. For example, Abca knock-out models have been crossed with transgenic mice in order to study their potential role in AD.^{54,123,131,161-163,527} These studies have elucidated potential disease mechanisms involving ABCA transporters that cannot be studied in patients.

Moreover, once a drug is developed and its specificity is proven, disease models enable evaluation of the role of that specific transporter in the pathophysiology of the disease. At the same time, these results may be the first step to evaluate the potential of novel transporter modulators as therapy for the respective disease.

Imaging techniques

Lastly, in vivo imaging can be used for the development of new drugs. On the one hand, labeling drug candidates with radioactive isotopes can give information about the drug distribution, drug target, and drug metabolism in vivo. In addition, it can also show whether a drug is able to cross specific natural barriers, such as the BBB. In vivo imaging can help to select candidates that appear successful or to discard drugs that seem likely to fail.⁵⁴⁶

On the other hand, drug candidates can also be used to develop new radiotracers (e.g., PET tracers) targeting ABCA transporters that could then be used in clinical diagnostics. Radiotracers would facilitate the study of the specific gene and/or its product protein in human patients in vivo and in a longitudinal fashion, enabling a much better understanding of the role of ABCA transporters in human (patho)physiology.⁵⁴⁷ In this regard, knock-out animals can be used as negative controls for the development of new ABCA radiotracers to evaluate the specificity of the radiotracer.⁵⁴⁸ Furthermore, these very same radiotracers can be used in animal disease models, enabling longitudinal studies and reducing the number of animals required.^549-551

CONCLUDING REMARKS: WHERE DO WE GO FROM HERE?

Several in vivo studies demonstrated that modulators of ABCA transporters, in particular ABCA1, have systemic effects.^{231,249,250,253,271,275,289,293,297,330,335,344,350,361,362,366,368-370,376,378,383,410,415,417-419,425,431,436,448} However, the vast majority of these modulators were regulators,^{231,250,253,271,297,330,335,344,350,361,362,366,368-370,
376,378,383,410,415,417-419,425,431,436,448} specifically inducers,^{250,253,271,297,330,344,361,362,366,368-370,376,378,383,410,
415,418,419,425,431} and only very few interactors demonstrated in vivo effects.^249,289,293 Mostly emphasizing atherosclerosis,^{249,275,289,366,369,370,378,410,417-419,425,431,448} these regulators were able to demonstrate that cellular and plasma lipid content^{249,271,275,289,330,366,369,378,419,425,431} as well as atherosclerotic plaque formation^{275,289,366,369,370,410, 417-419,425,448} could be changed compared to controls (enhanced or reduced) after treatment with the respective drug. Only very few in vivo approaches targeted for AD.^{293,297,344,383}

Taking the challenge of CNS penetration of these drugs into account, drugs active in atherosclerosis models could generally be suggested to also have certain therapeutic relevance regarding AD. Nevertheless, so far, none of these drugs has made it into clinical evaluation in humans. The underlying cause can be pinned to the fact that the principal mechanism by which ABCA transporters contribute to AD is still unknown. While a rationale can be found in atherosclerosis (efflux of cellular lipid to APOE and HDL resulting in lower lipid burden in the vascular system), the translation of this rationale to AD can only be achieved to a very limited extent. Several questions need addressing in future evaluations: (i) what is the general function of ABCA transporters in the brain to ameliorate (or exacerbate) AD in patients; (ii) when does this development start; and (iii) at which stage of development can a pharmacological intervention with ABCA transporter modulators lead to a positive therapeutic effect?

In this regard, more in vitro tests are needed with new lead structures that are rigorously assessed for their particular mechanism of action – to study vice versa the mechanism of action of ABCA transporters in general. One possibility to gain novel lead structures is the screening of huge analog compound libraries. However, the number of existing compounds is limited, and blind in vitro testing is resource-consuming, especially regarding time and funds. Computational methodologies may help to generate novel lead structures based on the knowledge of existing modulators of ABCA transporters. This has led to new lead molecules in the past.^{18,19,493,495} Particularly the knowledge on ABCA1 and ABCA8 inhibitors and substrates is of interest, because these compounds inherit the molecular-structural information that is critical for direct binding to these transporters. Considering the newly developed pattern analysis methodology, C@PA,^18,19,495 the scaffolds and substructural composition of this set of molecules may reveal the critical necessities for direct interaction with ABCA transporters. C@PA is therefore of high relevance because it was specifically developed to gain multitargeting pan-ABC transporter modulators^18,19,495 – molecules that particularly interact with different ABC transporters of different subfamilies. Assuming that a conserved multitarget binding site exists as proposed earlier,^6,14,475 multitargeting may be the key to explore under-studied ABC transporters in general and ABCA transporters in particular.^6,14,18,19 Several thousands of these molecules have already been predicted,^{18,19,493,495} and the predictions were in part biologically confirmed.^{18,19,493,495} Additionally, selected pan-ABC transporter inhibitors were analyzed in molecular docking studies, which revealed the potential existence of the multitarget binding site.⁴⁷⁵ Hence, combining the existent knowledge of ABCA transporter modulators with (sub)structural elements of these pan-ABC transporter modulators and powerful computational approaches (e.g., molecular docking or molecular dynamics simulations) could ultimately lead to the successful exploration of ABCA transporters in general, as well as ABCA1 and ABCA7 in particular.^{28,95,103-112}

Several drugs and drug-like compounds have already been demonstrated to be pan-ABC transporter modulators interacting also with ABCA transporters. These drugs and drug-like compounds are, for example, cyclosporine A (9 targets of 4 subfamilies: ABCA1,²⁴⁵ ABCB1,²⁰ ABCB4,⁵⁵² ABCB11,⁵⁵³ ABCC1–2,^24,554 ABCC10,²⁶ and ABCG1–2^555,556), glibenclamide (8 targets of 4 subfamilies: ABCA1,²⁷⁰ ABCB11,⁵⁵³ ABCC1,²⁴ ABCC5,⁵⁵⁷ ABCC7–9,^558-560 and ABCG2⁵⁵⁴), imatinib (6 targets of 4 subfamilies: ABCA3,⁴²⁶ ABCB1,⁵⁶¹ ABCB11,⁵⁵³ ABCC1,⁵⁶¹ ABCC10,⁵⁶¹ and ABCG2⁵⁶¹), probenecid (8 targets of 2 subfamilies: ABCA8,²²² ABCC1–6,^{24,26,562-564} ABCC10⁵⁶⁵), verapamil (9 targets of 4 subfamilies: ABCA8,²²² ABCB1,²⁰ ABCB4–5,^552,566 ABCB11,⁵⁶⁷ ABCC1,²⁴ ABCC4,⁵⁶⁸ ABCC10,⁵⁶⁵ and ABCG2⁵⁵⁴), and verlukast (11 targets of 4 subfamilies: ABCA8,²²² ABCB4,⁵⁵² ABCB11,⁵⁵³ ABCC1–5,^{24,554,557,564,569} ABCC10–11,^26,570 ABCG2⁵⁵⁴). In silico analyses with verapamil and verlukast supported the notion of addressing the multitarget binding site in ABCA7.⁴⁷⁵ Taking their structural peculiarities in a pattern-based rational drug design approach into account may yield novel lead structures for functional in vitro studies of ABCA transporters. This may ultimately result in the development of innovative AD diagnostics and therapeutics.

APPENDIX

Author information

Corresponding author

Sven Marcel Stefan, Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway;
ORCiD: 0000-0002-2048-8598
Email: s.m.stefan@medisin.uio.no

Authors

Jens Pahnke, 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;
ORCiD: 0000-0001-7355-4213

Pablo Bascuñana, Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway;
ORCiD: 0000-0003-2186-8899

Mirjam Brackhan, Department of Pathology, Section of Neuropathology, Translational Neurodeg-eneration 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;
ORCiD: 0000-0002-0753-6292

Katja Stefan, Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway;
ORCiD: 0000-0003-3544-2477

Vigneshwaran Namasivayam, Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany;
ORCiD: 0000-0003-3031-3377

Radosveta Koldamova, Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, 130 De Soto Street, Pittsburgh, PA 15261, United States of America;
ORCiD: 0000-0002-6761-0984

Jingyun Wu, Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway;
ORCiD: 0000-0002-5137-4614

Luisa Möhle, Department of Pathology, Section of Neuropathology, Translational Neurodege-neration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway;
ORCiD: 0000-0002-4535-9952

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

JP received funding from Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; Germany; 263024513); Latvian Council of Science (Latvia; LZP-2018/1-0275); HelseSØ (Norway; 2019054, 2019055); Barnekreftforeningen (Norway; 19008); EEA grant/Norway grants Kappa programme (Iceland, Liechtenstein, Norway; TAČR TARIMAD TO100078); Norges forskningsråd [Norway; 260786 (PROP-AD), 295910 (NAPI), and 327571 (PETABC)]; European Commission (European Union; 643417).

PROP-AD and PETABC are EU Joint Programme - Neurodegenerative Disease Research (JPND) projects. PROP-AD is supported through the following funding organizations under the aegis of JPND – www.jpnd.eu: AKA #301228 – Finland, BMBF #01ED1605 – Germany; CSO-MOH #30000-12631 – Israel; NFR #260786 – Norway; SRC #2015-06795 – Sweden). PETABC is supported through the following funding organizations under the aegis of JPND – www.jpnd.eu: NFR #327571 – Norway; FFG #882717 – Austria; BMBF #01ED2106 – Germany; MSMT #8F21002 – Czech Republic; VIAA #ES RTD/2020/26 – Latvia; ANR #20-JPW2-0002-04 – France, SRC #2020-02905 – Sweden. The projects receive funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement #643417 (JPco-fuND).

KS receives a Walter Benjamin fellowship of the DFG (Germany; 466106904).

RK is funded by the National Institute of Health (NIH; United States; AG056371, AG057565; AG066198).

LM is supported by the Norwegian Health Association (Nasjonalforeningen for folkehelsen; Norway; #16154).

SMS receives a Walter Benjamin fellowship of the DFG (Germany; 446812474).

Acknowledgement

The authors would like to cordially thank Joseph Mark Robertson (NAPI / Department of Immunology, University of Oslo and Oslo University Hospital) for proofreading the manuscript.

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