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ATP-binding cassette transporter A1: From metabolism to neurodegeneration
Open accessAbstract
ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential regulator of high density lipoproteins (HDL) and reverse cholesterol transport - a role that determines its importance for atherosclerosis. Over the last 10 years studies have provided convincing evidence that ABCA1, via its control of apoE lipidation, also has a role in Alzheimer's disease (AD). A series of reports have revealed a significant impact of ABCA1 on Aβ deposition and clearance in AD model mice, as well as an association of common and rare ABCA1 gene variants with the risk for AD. Since APOE is the major genetic risk factor for late onset AD, the regulation of apoE level or its functionality by ABCA1 may prove significant for AD pathogenesis. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptors (RXR) which provides a starting point for drug discovery and development of synthetic LXR and RXR agonists for treatment of metabolic and neurodegenerative disorders. This review summarizes the recent results of research on ABCA1, particularly relevant to atherosclerosis and AD.
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“In addition to its role in lipid transport, ABCA1 also indirectly facilitates amyloid β clearance through ApoE lipidation in brain [6].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [6]
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“Deletion of ABCA1 gene increases amyloid β accumulation, whereas its overexpression prevents amyloid β aggregation in amyloid mouse models [6].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [6]
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“Agonists of these nuclear receptors increased the levels of ABCA1 and decreased amyloid β accumulation in APP mouse models [6].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [6]
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“ATP-binding cassette transporter A1 (ABCA1) is a major cholesterol transporter that transfers cellular cholesterol onto lipid-poor apolipoproteins and regulates ApoE lipidation in the brain (Koldamova et al., 2014).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Koldamova et al., 2014
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“Previous animal studies demonstrated that improvement of ApoE lipidation inhibits amyloid deposition in APP mouse models.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [6]
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“Mouse models in which mice were genetically modified to lack specific ABC transporters have demonstrated that more types of ABC transporters are important for Aβ clearance, such as ABCA1 (Koldamova et al., 2014) and ABCC1 (Krohn et al.”
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“These lipoproteins, in turn, can be removed from the brain through lipoprotein receptor-related protein 1 (LRP1; Koldamova et al., 2014).”
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Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR
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Self-citationmicroRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain
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“ATP-binding cassette transporter A1 (ABCA1) is a major cholesterol transporter that transfers cellular cholesterol onto lipid-poor apolipoproteins and regulates ApoE lipidation in the brain (Koldamova et al., 2014).”
BackgroundStorti, F., Klee, K., Todorova, V., Steiner, R., Othman, A., van der Velde-Visser, S. D., Samardzija, M., Meneau, I., Barben, M., Karademir, D., et al. (2019) · eLife · doi:10.7554/elife.45100 · Cited by 99
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“Properly lipidated APOE containing lipid particles in the brain affect synaptogenesis, play an important role in binding Aβ and lipid species, and facilitate their clearance through the bloodbrain barrier and by microglia (reviewed in [4, 5]).”
BackgroundSelf-citationRemembering your A, B, C's: Alzheimer's disease and ABCA1
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Dehghani, R., Rahmani, F., & Rezaei, N. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0042 · Cited by 72
“Studies have also proposed that ABCA1 inhibits Aβ secretion in neuronal cells by moderating APP proteolysis and membrane lipid homeostasis (Koldamova et al., 2014).”
Midlife lipid and glucose levels are associated with Alzheimer's disease
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Targeting Nuclear Receptors in Neurodegeneration and Neuroinflammation
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“The ABCA1 transporter plays a crucial role in this process by transferring cholesterol to apolipoproteins, including apoE, thus regulating lipidation in the brain (Koldamova et al., 2014).”
BackgroundApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61
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“Transcriptional programs operate to mediate the longterm control of ABCA1 (Koldamova et al., 2014).”
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Turri, M., Marchi, C., Adorni, M. P., Calabresi, L., & Zimetti, F. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2022.159123 · Cited by 54
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Mitochondrial regulation of macrophage cholesterol homeostasis
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“As the lipidation status of apoE affects its function and receptorbinding capacity (Bu 2009; Koldamova et al. 2014), deficits in lipidation may underlie the pathogenic effects of apoE4.”
BackgroundSmall molecule inducers of ABCA1 and apoE that act through indirect activation of the LXR pathway
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“ABCA1 is a desirable therapeutic target for AD, as it mediates lipidation of apoE in the CNS and consistently demonstrates beneficial effects on cognition and neuropathology in multiple AD models (32).”
BackgroundFanaee‐Danesh, E., Gali, C. C., Tadić, J., Zandl‐Lang, M., Kober, A. C., Agujetas, V. R., de Dios, C., Tam‐Amersdorfer, C., Stracke, A., Albrecher, N. M., et al. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.04.019 · Cited by 53
Advances in high-density lipoprotein physiology: surprises, overturns, and promises
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“Recent experimental evidence revealed a significant decrease in neurite length and number of neurite segments in the CA1 region of the hippocampus of abca1 / mice, suggesting the importance of Abca1 in neurite degeneration in the brain (93).”
BackgroundPlasmalogen deficiency and neuropathology in Alzheimer's disease: Causation or coincidence?
Senanayake, V. K., & Goodenowe, D. B. (2019) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.08.003 · Cited by 51
“In addition to preventing Ab oligomer formation and inducing Ab degradation, lipidated apoE promotes Ab efflux via bloodbrain barrier and might enhance peripheral clearance through apoE-containing HDL particles [38].”
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“…of patients with non-functional ABCA1 and Abca1 knockout mice (Abca1ko) is their virtual absence of circulating high density lipoproteins and ApoA-I in plasma and brain, and relatively low level of low density lipoproteins in the blood (Brooks-Wilson et al., 1999; Koldamova et al., 2014).”
BackgroundInfluentialSelf-citationRNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment
Lefterov, I. M., Schug, J., Mounier, A., Nam, K. N., Fitz, N. F., & Koldamova, R. P. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.05.019 · Cited by 36
“…heterodimers in in vivo and in vitro models of Alzheimer's disease (AD) was first demonstrated a decade ago using partially specific LXR or PPARγ agonists (Heneka et al., 2005; Koldamova et al., 2003; Koldamova et al., 2005) and later confirmed in numerous studies (Koldamova et al., 2014a).”
BackgroundSelf-citationCoisne, C., Hallier-Vanuxeem, D., Boucau, M., Hachani, J., Tilloy, S., Bricout, H., Monflier, É., Wils, D., Serpelloni, M., Parissaux, X., et al. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00185 · Cited by 36
“…or when cells are loaded with cholesterol, transcriptional expressions of ABCA1, and ABCG1 are induced and lead to an increase in cholesterol release to ApoA-I, ApoE, or HDL (Hirsch-Reinshagen and Wellington, 2007; Saint-Pol et al., 2012, 2013; Gosselet et al., 2014; Koldamova et al., 2014).”
BackgroundKloske, C. M., Belloy, M. E., Blue, E. E., Bowman, G. R., Carrillo, M. C., Chen, X., Chiba‐Falek, O., Davis, A. A., Paolo, G. D., Garretti, F., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13877 · Cited by 33
“53 In high-density lipoprotein (HDL) particles, apoA1 binds ABCA1, leading to the translocation of cholesterol across the phospholipid bilayer membrane, thereby regulating cholesterol efflux.”
BackgroundImpact of natural products on the cholesterol transporter ABCA1
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Relation between plasma and brain lipids
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“Conversely, drugs that enhance Abca1 levels promote clearance of Aβ through elevations in lipidated ApoEHDL particles and enhance cognition [25].”
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“That being said, Tsimane show very low HDL levels: 57% of adults would be considered at-risk given the usual recommendations of >40 mg/dL (22, 73).”
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ABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice
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“ATP binding cassette transporter A1 (ABCA1) regulates cholesterol and phospholipids efflux from cells to lipid-poor apolipoprotein A-I (ApoA-I) and ApoE and controls the generation of high density lipoproteins (HDL) (reviewed in [6]).”
Self-citationPahnke, J., Bascuñana, P., Brackhan, M., Stefan, K., Namasivayam, V., Koldamova, R. P., Wu, J., Möhle, L., & Stefan, S. M. (2021) · Free Neuropathology · doi:10.17879/freeneuropathology-2021-3528 · Cited by 29
Self-citationThe novel function of bexarotene for neurological diseases
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Aging reduces glial uptake and promotes extracellular accumulation of Aβ from a lentiviral vector
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“…primarily and perhaps exclusively neuronal, we propose the large amount of microglial Aβ results from the combination of efflux of Aβ from neurons [perhaps through mechanisms relating to the cholesterol efflux molecule, ABC-A1 (Koldamova et al., 2014)], and then the subsequent uptake by microglia.”
BackgroundCarter, A. Y., Letronne, F., Fitz, N. F., Mounier, A., Wolfe, C. M., Nam, K. N., Reeves, V. L., Kamboh, H., Lefterov, I., & Koldamova, R. (2017) · PLOS ONE · doi:10.1371/journal.pone.0172161 · Cited by 28
Self-citationAPOE4 is a Risk Factor and Potential Therapeutic Target for Alzheimer's Disease
Ayyubova, G. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230303114425 · Cited by 23
Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes
Fan, J., Zareyan, S., Zhao, W., Shimizu, Y., Pfeifer, T. A., Tak, J., Isman, M. B., den Hoven, B. G. V., Duggan, M. E., Wood, M. W., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162384 · Cited by 24
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“transporter A1 (ABCA1), and the nuclear liver X receptors (LXR) have similarly played a major role in the clearance of soluble Aβ (2).”
BackgroundCastranio, E. L., Wolfe, C. M., Nam, K. N., Letronne, F., Fitz, N. F., Lefterov, I., & Koldamova, R. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0569-2 · Cited by 23
“ABCA1 is a major regulator of cholesterol transport and an essential mediator of high density lipoprotein generation [22].”
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APOEε4 and risk of Alzheimer’s disease – time to move forward
Lefterov, I. M., Fitz, N. F., Lü, Y., & Koldamova, R. P. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1195724 · Cited by 25
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Scientific and technological challenges of recombinant egg protein production
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DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously
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“It has an established role in the regulation of HDL and there are reports that common variants in it are associated with plasma lipid levels (Koldamova et al., 2014; Lu et al., 2018).”
BackgroundEmerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers
Han, N., Yuan, M., Yan, L., & Tang, H. (2023) · Biomolecules · doi:10.3390/biom13081184 · Cited by 15
“LXRα may be involved in various signaling pathways by repressing or inducing the expression of these genes to maintain normal physiological activity, such as the ATP-binding cassette transporter A1 (ABCA1) and Niemann–Pick type C1 [4,5].”
BackgroundGlibenclamide as a neuroprotective antidementia drug
Zubov, A. S., Muruzheva, Z. M., Tikhomirova, M. S., & Karpenko, M. N. (2020) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2020.1789170 · Cited by 15
“In particular they ensure delivery of cholesterol from astrocytes to neurons (Koldamova et al. 2014).”
BackgroundSierri, G., Dal Magro, R., Vergani, B., Leone, B. E., Formicola, B., Taiarol, L., Fagioli, S., Kravicz, M., Tremolizzo, L., Calabresi, L., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010102 · Cited by 16
“Experiments on AD-like transgenic mice have demonstrated that silencing ABCA1 decreases the lipidation of apoE, increases the deposition of Aβ, and reduces drastically high-density lipoproteins’ (HDLs) levels in the brain parenchyma and in the cerebrospinal fluid (CSF) [8,9].”
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“A series of evidences indicate that deficiency of ABCA1 induce an obvious decrease of apoE level, coupled with increase of β -amyloid deposition in AD-like mice, which is associated with rare ABCA1 gene variants (Koldamova et al., 2014; Borr ` as et al., 2022).”
Epigenetic Regulation of Amyloid-beta Metabolism in Alzheimer’s Disease
He, C., Huang, Z., Yu, C.-C., Wang, H., Zhou, H., & Kong, L.-H. (2020) · Current Medical Science · doi:10.1007/s11596-020-2283-0 · Cited by 11
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“Although the normal physiological role of ABCA1 in the CNS remains less than clear [32, 42], it has”
ABCA7 Loss-of-Function Variants Impact Phosphatidylcholine Metabolism in the Human BrainPreprint
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“…(Bryleva et al., 2010) (Figure 3b), or Abca1, the transmembrane protein that transfers cholesterol to lipid‐free apolipoproteins such as ApoE to facilitate efflux of the ApoE‐ cholesterol complex from astrocytes for entry into neurons for degradation by Cyp46a1 (Koldamova et al., 2014) (Figure 3c).”
BackgroundWu, J., Yu, X., Xue, K., Wu, J., Wang, R., Xie, X., Li, K., Yang, Z., & Yue, J. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/8735249 · Cited by 8
“Previous data revealed a significant decrease in the length of neurites and the number of neurite segments in the hippocampal CA1 region of ABCA1 knockout mice compared to those in the hippocampal CA1 region of wild-type mice, suggesting the importance of ABCA1 disruption for neurite degeneration in the brain [5].”
ResultLCAT deficiency does not impair amyloid metabolism in APP/PS1 mice
Stukas, S., Freeman, L., Lee, M., Wilkinson, A., Ossoli, A., Vaisman, B., Demosky, S., Chan, J., Hirsch-Reinshagen, V., Remaley, A. T., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m049940 · Cited by 9
Epigenetic changes induced by pathogenic Chlamydia spp
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Role of Nuclear Receptors on the Progression of Multiple Sclerosis: A Review
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“In vitro studies have demonstrated that ABCA1 and ABCG1 in the cell membrane are necessary to eliminate cholesterol and protect neurons by suppressing cell death, inflammation, and oxidative stress (Koldamova et al. 2014).”
Sarlak, Z., Moazzami, M., Hosseini, S. R. A., & Gharakhanlou, R. (2019) · PubMed · doi:10.22038/ijbms.2018.32911.7860 · Cited by 7
“The expression of ABCA1 and APOE is regulated by nuclear receptors, the peroxisome proliferator-activated receptor γ (PPAR-γ), and the liver X receptors (LXRs) (21, 44).”
BackgroundWu, D., Hu, Y., Song, M., & Li, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.634948 · Cited by 7
“Interestingly, dysfunctional ABCA1 contributes to the development of type 2 diabetes through increased cholesterol levels in pancreatic β-cells (Koldamova et al., 2014).”
BackgroundFat and Lipid Metabolism and the Involvement of Apolipoprotein E in Alzheimer's Disease
Hone, E., Lim, F., & Martins, I. J. (2019) · Wiley eBooks · doi:10.1002/9781119356752.ch7 · Cited by 8
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“factor, liver X receptor [20], which upregulates the ABCA1 protein [34,52].”
BackgroundNowacka, A., Śniegocki, M., & Ziółkowska, E. (2025) · Cells · doi:10.3390/cells14181479 · Cited by 5
“These transporters are expressed across neural cell types and link intracellular sterol pools to extracellular lipoprotein dynamics [87].”
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Lipids and Lipoproteins in Alzheimer’s Disease
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“In the brain, ABCA1 modulates ApoE metabolism, and its defi - ciency is involved in amyloid beta aggregation, toxicity and clearance [18 ].”
Gene expression profiles of HTR8-S/Vneo cells after changes in ABCA1 expression
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Potential Role of ABCF2 Gene in Pudendal Nerve Neuropathy and Interstitial Cystitis
Musumeci, A., Vinci, M., Treccarichi, S., Ragalmuto, A., Bruno, G., Tinnirello, G., Farina, J., Federico, C., Saccone, S., Calı̀, F., et al. (2025) · Genes · doi:10.3390/genes16030281 · Cited by 3
“As extensively reported, there is a well-established correlation between defects in genes involved in ATP metabolism and neuropathy [32].”
Metadata
- Authors
- Koldamova, R., Fitz, N. F., & Lefterov, I.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Koldamova, Radosveta
- Lefterov, Iliya
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 72
- Pages
- 13-21
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC4302328
- OpenAlex
- W2013375919
- Cited by
- 144
- References
- 146
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 6 · 2023: 18 · 2022: 12 · 2021: 12 · 2020: 6 · 2019: 12 · 2018: 11 · 2017: 11 · 2016: 10 · 2015: 11 · 2014: 2
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIH (R01AG037481, R01AG037919, R21ES021243, K01AG044490)
- DOD (W81XWH-13-1-0384)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- ABCA1, ABC transporters, Alzheimer's disease, atherosclerosis, reverse cholesterol transport, high-density lipoprotein, apolipoprotein E, apolipoprotein A-I, amyloid-beta clearance, liver X receptor, retinoid X receptor, LXR agonists, RXR agonists, cholesterol efflux, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Humans, Risk Factors, Tangier Disease, Amyloid beta-Peptides, Atherosclerosis, Mice, ATP Binding Cassette Transporter 1
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