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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ABCA1 indirectly facilitates amyloid β clearance through ApoE lipidation in brain.
“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]
The Introduction says ABCA1 affects apoE lipidation and that apoE is implicated in Aβ clearance. In “ABCA1 and AD model mice,” the authors propose that ABCA1-generated apoE-containing particles facilitate clearance in the brain, but present that specific mechanism as a hypothesis rather than an established fact. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDeletion of ABCA1 gene increases amyloid β accumulation, whereas its overexpression prevents amyloid β aggregation in amyloid mouse models.
“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]
The “ABCA1 and AD model mice” section reports that ABCA1 deficiency increases amyloid plaques and that mice overexpressing ABCA1 in the brain have fewer plaques. It proposes decreased Aβ aggregation as a hypothesis, but does not establish that overexpression prevents aggregation. Page numbers were not provided. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAgonists of nuclear receptors LXR, RXR, and PPAR increased the levels of ABCA1 and decreased amyloid β accumulation in APP mouse models.
“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]
The “ABCA1 and Alzheimer’s disease” section reports that LXR and RXR ligands increase Abca1 expression in mice and ameliorate amyloid pathology; “Therapeutic implications” discusses these effects in APP mice. The paper says PPARs regulate ABCA1 transcription, but does not report that PPAR agonists both increased ABCA1 and decreased amyloid accumulation in APP mice. It also notes that follow-up studies did not confirm the reported plaque reduction with the RXR agonist bexarotene. (LLM, conf=0.88)
Experimental — accuracy not yet measuredABCA1 is a major cholesterol transporter that transfers cellular cholesterol onto lipid-poor apolipoproteins and regulates ApoE lipidation in the brain.
“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
Improvement of ApoE lipidation inhibits amyloid deposition in APP mouse models.
“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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Genetic Defects in Lipoprotein Metabolism
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Association of ATP-Binding Cassette Transporter Variants With the Risk of Alzheimer‘s Disease
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- Wahrle SE 2008b Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease J Clin Invest 118 671 82 18202749 PMC2200302
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Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease
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Cummings, J. L., Zhong, K., Kinney, J. W., Heaney, C., Moll-Tudla, J., Joshi, A., Pontecorvo, M., Devous, M., Tang, A., & Bena, J. (2016) · Alzheimer's Research & Therapy · doi:10.1186/s13195-016-0173-2 · Cited by 190 · see citing works
“Lipidation is determined by the ATP-binding cassette A1 (ABCA1), which is in turn under the control of nuclear retinoid X receptors (RXRs) [9, 11, 12].”
BackgroundThe Role of APOE and TREM2 in Alzheimer′s Disease—Current Understanding and Perspectives
Wolfe, C. M., Fitz, N. F., Nam, K. N., Lefterov, I. M., & Koldamova, R. P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010081 · Cited by 192 · see citing works
“ABCA1 transports cholesterol and phospholipids to lipid-free APOE, thus forming discoidal HDL particles (reviewed in [25,26]).”
BackgroundSelf-citationHorgusluoglu, E., Neff, R., Song, W., Wang, M., Wang, Q., Arnold, M., Krumsiek, J., Galindo‐Prieto, B., Ming, C., Nho, K., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12468 · Cited by 175 · see citing works
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Interaction between blood-brain barrier and glymphatic system in solute clearance
Verheggen, I. C. M., van Boxtel, M. P. J., Verhey, F. R. J., Jansen, J. F. A., & Backes, W. H. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.03.028 · Cited by 170 · see citing works
“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.”
BackgroundThe role of APOE on lipid homeostasis and inflammation in normal brains
Rebeck, G. W. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075408 · Cited by 160 · see citing works
“accumulate lipid from a cellular efflux mechanism with the ABCA1 transporter (29).”
BackgroundIntracellular Cholesterol Trafficking and Impact in Neurodegeneration
Arenas, F., García‐Ruiz, C., & Fernández-Checa, J. C. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00382 · Cited by 161 · see citing works
“These lipoproteins, in turn, can be removed from the brain through lipoprotein receptor-related protein 1 (LRP1; Koldamova et al., 2014).”
BackgroundMillan, M. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.004 · Cited by 146 · see citing works
Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR
Hiebl, V., Ladurner, A., Latkolik, S. L., & Dirsch, V. M. (2018) · Biotechnology Advances · doi:10.1016/j.biotechadv.2018.03.003 · Cited by 135 · see citing works
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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 97 · see citing works
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Brain metabolism in Alzheimer’s disease: biological mechanisms of exercise
Xu, L., Liu, R., Qin, Y., & Wang, T. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00364-y · Cited by 78 · see citing works
APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain
Lefterov, I., Wolfe, C. M., Fitz, N. F., Nam, K. N., Letronne, F., Biedrzycki, R. J., Kofler, J., Han, X., Wang, J., Schug, J., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0558-0 · Cited by 74 · see citing works
“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
Lewandowski, C. T., Laham, M. S., & Thatcher, G. R. J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.011 · Cited by 76 · see citing works
MicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms
Dehghani, R., Rahmani, F., & Rezaei, N. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0042 · Cited by 72 · see citing works
“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
Zhang, X., Tong, T., Chang, A., Ang, T. F. A., Tao, Q., Auerbach, S., Devine, S., Qiu, W. Q., Mez, J., Massaro, J., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12641 · Cited by 65 · see citing works
Targeting Nuclear Receptors in Neurodegeneration and Neuroinflammation
Willems, S., Zaienne, D., & Merk, D. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00186 · Cited by 66 · see citing works
Yuan, T., Chu, C., Shi, R., Cui, T., Zhang, X., Zhao, Y., Shi, X., Yan, H., Pan, J., Qian, R., et al. (2019) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.9b01436 · Cited by 64 · see citing works
Cao, Y., Zhao, L., Chen, Z., & Li, S. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1430465 · Cited by 58 · see citing works
“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 · see citing works
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Li, L., Xu, L., Chen, W., Li, X., Xia, Q., Zheng, L., Duan, Q., Zhang, H., & Zhao, Y. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00347 · Cited by 56 · see citing works
“Transcriptional programs operate to mediate the longterm control of ABCA1 (Koldamova et al., 2014).”
BackgroundEmerging role of HDL in brain cholesterol metabolism and neurodegenerative disorders
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 · see citing works
Overview of the blood biomarkers in Alzheimer's disease: Promises and challenges
Delaby, C., Hirtz, C., & Lehmann, S. (2022) · Revue Neurologique · doi:10.1016/j.neurol.2022.09.003 · Cited by 56 · see citing works
Mitochondrial regulation of macrophage cholesterol homeostasis
Graham, A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.08.010 · Cited by 54 · see citing works
Zhao, Z.-W., Zhang, M., Chen, L., Gong, D., Xia, X.-D., Yu, X.-H., Wang, S., Ou, X., Dai, X.-Y., Zheng, X., et al. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2018.04.011 · Cited by 53 · see citing works
Chernick, D., Ortiz‐Valle, S., Jeong, A., Swaminathan, S. K., Kandimalla, K. K., Rebeck, G. W., & Li, L. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14554 · Cited by 53 · see citing works
“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
Fan, J., Zhao, R. Q., Parro, C., Zhao, W., Chou, H.-Y., Robert, J., Deeb, T. Z., Raynoschek, C., Barichievy, S., Engkvist, O., et al. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m081851 · Cited by 50 · see citing works
“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 52 · see citing works
Advances in high-density lipoprotein physiology: surprises, overturns, and promises
Constantinou, C., Karavia, E. A., Xepapadaki, E., Πετροπούλου, Π.-Ι., Παπακώστα, Ε., Karavyraki, M., Zvintzou, E., Theodoropoulos, V., Filou, S., Hatziri, A., et al. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00429.2015 · Cited by 48 · see citing works
“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 50 · see citing works
“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].”
BackgroundLi, Y., Meng, S., Wu, D., Xia, M., Dong, L., Zhao, Y., Ling, S., He, J. N., Xue, X., Chen, X., et al. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13846 · Cited by 48 · see citing works
Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer’s Disease
Campos-Peña, V., Pichardo-Rojas, P., Sánchez-Barbosa, T., Ortíz-Islas, E., Rodríguez-Pérez, C., Montes, P., Ramos-Palacios, G., Silva-Adaya, D., Valencia-Quintana, R., Cerna-Cortés, J. F., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012092 · Cited by 41 · see citing works
Sex Hormone Decline and Amyloid β Synthesis, Transport and Clearance in the Brain
Duarte, A. C., Hrynchak, M. V., Gonçalves, I., Quintela, T., & Santos, C. R. A. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12432 · Cited by 40 · see citing works
Li, G., Kim, C., Kim, J., Yoon, H., Zhou, H., & Kim, J. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-150024 · Cited by 39 · see citing works
Fitz, N. F., Tapias, V., Cronican, A. A., Castranio, E. L., Saleem, M., Carter, A. Y., Lefterova, M. I., Lefterov, I. M., & Koldamova, R. P. (2015) · Brain · doi:10.1093/brain/awv293 · Cited by 37 · see citing works
“…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 · see citing works
“…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 35 · see citing works
“…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 · see citing works
“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
Wang, D., Hiebl, V., Xu, T., Ladurner, A., Atanasov, A. G., Heiß, E. H., & Dirsch, V. M. (2019) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2019.112444 · Cited by 34 · see citing works
Relation between plasma and brain lipids
Wellington, C. L., & Frikke-Schmidt, R. (2016) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000291 · Cited by 33 · see citing works
Yang, D.-S., Stavrides, P. H., Kumar, A. R., Jiang, Y., Mohan, P. S., Ohno, M., Dobrenis, K., Davidson, C. D., Saito, M., Pawlik, M., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx001 · Cited by 31 · see citing works
Casali, B. T., Reed-Geaghan, E. G., & Landreth, G. E. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1091-y · Cited by 30 · see citing works
“Conversely, drugs that enhance Abca1 levels promote clearance of Aβ through elevations in lipidated ApoEHDL particles and enhance cognition [25].”
Lea, A. J., García, A. R., Arevalo, J. M. G., Ayroles, J. F., Buetow, K. H., Cole, S. W., Rodríguez, D. E., Cayuba, M. G., Highland, H. M., Hooper, P. L., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207544120 · Cited by 29 · see citing works
“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).”
InfluentialBi, X., Vitali, C., & Cuchel, M. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.305547 · Cited by 30 · see citing works
Differential effects of apoE4 and activation of ABCA1 on brain and plasma lipoproteins
Boehm-Cagan, A., Bar, R., Harats, D., Shaish, A., Levkovitz, H., Bielicki, J. K., Johansson, J. O., & Michaelson, D. M. (2016) · PLOS ONE · doi:10.1371/journal.pone.0166195 · Cited by 29 · see citing works
Crosstalk between Alzheimer’s disease and diabetes: a focus on anti-diabetic drugs
Goodarzi, G., Tehrani, S. S., Fana, S. E., Moradi‐Sardareh, H., Panahi, G., Maniati, M., & Meshkani, R. (2023) · Metabolic Brain Disease · doi:10.1007/s11011-023-01225-3 · Cited by 28 · see citing works
Seneviratne, U. I., Huang, Z., Ende, C. W. A., Butler, T. W., Cleary, L., Dresselhaus, E. C., Evrard, E., Fisher, E. L., Green, M. E., Helal, C. J., et al. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.09.002 · Cited by 28 · see citing works
Transporters as Drug Targets in Neurological Diseases
Qosa, H., Mohamed, L., Alqahtani, S., Abuasal, B., Hill, R., & Kaddoumi, A. (2016) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.435 · Cited by 28 · see citing works
ABCA1 rs2230805 and rs2230806 common gene variants are associated with Alzheimer’s disease
Fehér, Á., Giricz, Z., Juhász, A., Pákáski, M., Janka, Z., & Kalman, J. L. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.11.027 · Cited by 29 · see citing works
ABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice
Fitz, N. F., Carter, A. Y., Tapias, V., Castranio, E. L., Kodali, R. B., Lefterov, I. M., & Koldamova, R. P. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161056 · Cited by 26 · see citing works
“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 27 · see citing works
Self-citationThe novel function of bexarotene for neurological diseases
Liu, Y., Wang, P., Jin, G., Shi, P., Zhao, Y., Guo, J., Yin, Y., Shao, Q.-H., Li, P., & Yang, P. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102021 · Cited by 28 · see citing works
Aging reduces glial uptake and promotes extracellular accumulation of Aβ from a lentiviral vector
Zhao, W., Zhang, J., Davis, E. G., & Rebeck, G. W. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00210 · Cited by 25 · see citing works
“…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. M., & Koldamova, R. P. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172161 · Cited by 25 · see citing works
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 · see citing works
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 · see citing works
Wang, L., Liu, W., Fan, Y., Liu, T., & Yu, C. (2017) · Europe PMC (PubMed Central) · doi:10.22038/ijbms.2017.8669 · Cited by 24 · see citing works
“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 · see citing works
“ABCA1 is a major regulator of cholesterol transport and an essential mediator of high density lipoprotein generation [22].”
Self-citationXu, H., Zheng, L., Chen, X., Pang, Q., Yan, Y., Liu, R., Guo, H., Ren, Z., Yang, Y., Gu, Z., et al. (2022) · Brain Pathology · doi:10.1111/bpa.13126 · Cited by 21 · see citing works
Sun, D., Bo, L., Jiang, C., Lan, Y., Zhang, B., Zhang, C., Chen, Z., & Fan, Y. (2025) · Drug Resistance Updates · doi:10.1016/j.drup.2025.101310 · Cited by 21 · see citing works
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 23 · see citing works
Self-citationMartens, N., Zhan, N., Voortman, G. J., Leijten, F. P. J., van Rheenen, C., van Leerdam, S., Geng, X., Huybrechts, M., Liu, H., Jonker, J. W., et al. (2023) · Nutrients · doi:10.3390/nu15133004 · Cited by 20 · see citing works
Scientific and technological challenges of recombinant egg protein production
Beck, F., Noll, P., Schweiggert‐Weisz, U., & Henkel, M. (2025) · BMC Biotechnology · doi:10.1186/s12896-025-01002-3 · Cited by 17 · see citing works
Gehlot, P., Pathak, R., Kumar, S., Choudhary, N. K., & Vyas, V. K. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117925 · Cited by 16 · see citing works
DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously
Smith, M. (2017) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2017.00024 · Cited by 16 · see citing works
Curtis, D. (2021) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2021-107752 · Cited by 16 · see citing works
“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 · see citing works
“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 · see citing works
“In particular they ensure delivery of cholesterol from astrocytes to neurons (Koldamova et al. 2014).”
BackgroundSierri, G., Magro, R. D., 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 15 · see citing works
“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].”
BackgroundReddy, V. G., Laham, M. S., Lewandowski, C. T., Valencia‐Olvera, A. C., Balu, D., Moore, A., Ackerman-Berrier, M. S., Rychetsky, P., Penton, C., Musku, S. R., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00733 · Cited by 14 · see citing works
Dib, S., Loiola, R. A., Sevin, E., Saint‐Pol, J., Shimizu, F., Kanda, T., Pahnke, J., & Gosselet, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065992 · Cited by 14 · see citing works
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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
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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).”
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“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. K., Freeman, L. A., Lee, M., Wilkinson, A., Ossoli, A., Vaisman, B. L., Demosky, S. J., Chan, J. Y., Hirsch‐Reinshagen, V., Remaley, A. T., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m049940 · Cited by 8 · see citing works
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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).”
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“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).”
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“Interestingly, dysfunctional ABCA1 contributes to the development of type 2 diabetes through increased cholesterol levels in pancreatic β-cells (Koldamova et al., 2014).”
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“factor, liver X receptor [20], which upregulates the ABCA1 protein [34,52].”
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“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 · see citing works
“As extensively reported, there is a well-established correlation between defects in genes involved in ATP metabolism and neuropathy [32].”
- 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
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › 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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