Role of ABCG1 and ABCA1 in Regulation of Neuronal Cholesterol Efflux to Apolipoprotein E Discs and Suppression of Amyloid-β Peptide Generation
Open accessAbstract
Maintenance of an adequate supply of cholesterol is important for neuronal function, whereas excess cholesterol promotes amyloid precursor protein (APP) cleavage generating toxic amyloid-beta (Abeta) peptides. To gain insights into the pathways that regulate neuronal cholesterol level, we investigated the potential for reconstituted apolipoprotein E (apoE) discs, resembling nascent lipoprotein complexes in the central nervous system, to stimulate neuronal [3H]cholesterol efflux. ApoE discs potently accelerated cholesterol efflux from primary human neurons and cell lines. The process was saturable (17.5 microg of apoE/ml) and was not influenced by APOE genotype. High performance liquid chromatography analysis of cholesterol and cholesterol metabolites effluxed from neurons indicated that <25% of the released cholesterol was modified to polar products (e.g. 24-hydroxycholesterol) that diffuse from neuronal membranes. Thus, most cholesterol (approximately 75%) appeared to be effluxed from neurons in a native state via a transporter pathway. ATP-binding cassette transporters ABCA1, ABCA2, and ABCG1 were detected in neurons and neuroblastoma cell lines and expression of these cDNAs revealed that ABCA1 and ABCG1 stimulated cholesterol efflux to apoE discs. In addition, ABCA1 and ABCG1 expression in Chinese hamster ovary cells that stably express human APP significantly reduced Abeta generation, whereas ABCA2 did not modulate either cholesterol efflux or Abeta generation. These data indicate that ABCA1 and ABCG1 play a significant role in the regulation of neuronal cholesterol efflux to apoE discs and in suppression of APP processing to generate Abeta peptides.
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Most studies demonstrated that ABCA1 induction decreases the levels of Aβ and CTFβ.
“Most of studies demonstrated that ABCA1 induction decreases the levels of Aβ and CTFβ (Kim et al., 2007; Koldamova et al., 2003; Sun et al., 2003).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Kim et al., 2007
In “Regulation of Aβ Peptide Generation by ABCG1” (page unavailable), the paper reports that ABCA1 expression reduced Aβ generation by 55% in CHO-APP cells. It does not report a decrease in CTFβ, so it supports only the Aβ portion of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredABCA1 induction by LXR agonist decreases Aβ production in various cell lines.
“ABCA1 induction by liver X receptor (LXR) agonist decreased Aβ production in various cell lines (Kim et al., 2007; Koldamova et al., 2003; Sun et al., 2003).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Kim et al., 2007
The Results section reports that ABCA1 transfection reduced Aβ generation in CHO-APP cells. The Discussion also describes a previous CHO-cell study in which an LXR agonist induced ABCA1 expression and apoA-I inhibited Aβ generation. This paper does not establish that LXR-agonist induction decreased Aβ production across various cell lines. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLXR agonists TO901317 and GW3965 alter Aβ production in neuronal and non-neuronal cell cultures overexpressing APP.
“It has been shown that the LXR agonists TO901317 and GW3965 alter amyloid- (A) production in neuronal and non-neuronal cell cultures overexpressing amyloid precursor protein (APP)”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Kim et al., 2007
The Discussion (page unavailable) reports that TO901317 treatment was associated with reduced Aβ generation in APP-expressing CHO cells, a non-neuronal culture. It does not report GW3965 or show that either agonist alters Aβ production in neuronal cultures. The paper’s own CHO-APP experiments tested ABCG1 and ABCA1 expression, not these agonists. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn vitro evidence supports a critical role of ABCA1 in Aβ production.
“Furthermore, several lines of in vitro evidence support the critical role of ABCA1 in A production, although how ABCA1 regulates A production remains to be clarified (Koldamova et al., 2003;Sun et al., 2003;Kim et al., 2007).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Kim et al., 2007
ABCA1 has a critical role in Aβ metabolism and accumulation.
“Several lines of data strongly support that ABCA1 has a critical role in Aβ metabolism and accumulation.”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Kim et al., 2007
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1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · see citing works
RetractedNeuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619 · see citing works
Lund, E. G., Xie, C., Kotti, T., Turley, S. D., Dietschy, J. M., & Russell, D. W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303415200 · Cited by 421 · see citing works
Nascent astrocyte particles differ from lipoproteins in CSF
LaDu, M. J., Gilligan, S. M., Lukens, J. R., Cabana, V. G., Reardon, C. A., Van Eldik, L. J., & Holtzman, D. M. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70052070.x · Cited by 285 · see citing works
White, A. R., Du, T., Laughton, K. M., Volitakis, I., Sharples, R. A., Xilinas, M. E., Hoke, D. E., Holsinger, R. M. D., Evin, G., Cherny, R. A., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602487200 · Cited by 284 · see citing works
Self-citationKoldamova, R. P., Lefterov, I. M., Staufenbiel, M., Wolfe, D., Huang, S., Glorioso, J. C., Walter, M., Roth, M. G., & Lazo, J. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411420200 · Cited by 279 · see citing works
TOKUDA, T., CALERO, M., MATSUBARA, E., VIDAL, R., KUMAR, A., PERMANNE, B., ZLOKOVIC, B., SMITH, J. D., LADU, M. J., ROSTAGNO, A., et al. (2000) · Biochemical Journal · doi:10.1042/bj3480359 · Cited by 272 · see citing works
Hirsch-Reinshagen, V., Maia, L. F., Burgess, B. L., Blain, J.-F., Naus, K. E., McIsaac, S. A., Parkinson, P. F., Chan, J. Y., Tansley, G. H., Hayden, M. R., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508781200 · Cited by 233 · see citing works
Fagan, A. M., Holtzman, D. M., Munson, G., Mathur, T., Schneider, D., Chang, L. K., Getz, G. S., Reardon, C. A., Lukens, J., Shah, J. A., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30001 · Cited by 222 · see citing works
Gong, J.-S., Kobayashi, M., Hayashi, H., Zou, K., Sawamura, N., Fujita, S. C., Yanagisawa, K., & Michikawa, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203934200 · Cited by 214 · see citing works
Glycosphingolipid Accumulation Inhibits Cholesterol Efflux via the ABCA1/Apolipoprotein A-I Pathway
Glaros, E. N., Kim, W. S., Quinn, C. M., Wong, J., Gelissen, I., Jessup, W., & Garner, B. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413862200 · Cited by 75 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 6
- Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C. G., and Simons, K. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 6460 -6464
- Lund, E. G., Guileyardo, J. M., and Russell, D. W. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 7238 -7243
- Lutjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Siden, A., Dicz- falusy, U., and Bjorkhem, I. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9799 -9804
- Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., and Pericak-Vance, M. A. (1993) Science 261, 921-923
- Klucken, J., Buchler, C., Orso, E., Kaminski, W. E., Porsch-Ozcurumez, M., Liebisch, G., Kapinsky, M., Diederich, W., Drobnik, W., Dean, M., Allik- mets, R., and Schmitz, G. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 817-822
- Wang, L., Schuster, G. U., Hultenby, K., Zhang, Q., Andersson, S., and Gustafsson, J. A. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 13878 -13883
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Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., Pasolli, H. A., Xu, C. S., Pang, S., Matthies, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.001 · Cited by 760 · see citing works
Cholesterol metabolism in neurons and astrocytes
Pfrieger, F. W., & Ungerer, N. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2011.06.002 · Cited by 500 · see citing works
Terwel, D., Steffensen, K. R., Verghese, P. B., Kummer, M. P., Gustafsson, J.-Å., Holtzman, D. M., & Heneka, M. T. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6546-10.2011 · Cited by 181 · see citing works
miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression
Kim, J., Yoon, H., Ramírez, C. M., Lee, S.-M., Hoe, H.-S., Fernández-Hernando, C., & Kim, J. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2011.11.010 · Cited by 173 · see citing works
Brain cholesterol in normal and pathological aging
Martin, M., Dotti, C. G., & Ledesma, M. D. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.03.011 · Cited by 162 · see citing works
ATP-binding cassette transporter A1: From metabolism to neurodegeneration
Koldamova, R., Fitz, N. F., & Lefterov, I. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.007 · Cited by 144 · see citing works
microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain
Kim, J., Yoon, H., Horie, T., Burchett, J. M., Restivo, J. L., Rotllan, N., Ramírez, C. M., Verghese, P. B., Ihara, M., Hoe, H.-S., et al. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2053-15.2015 · Cited by 128 · see citing works
“Furthermore, several lines of in vitro evidence support the critical role of ABCA1 in A production, although how ABCA1 regulates A production remains to be clarified (Koldamova et al., 2003; Sun et al., 2003; Kim et al., 2007).”
BackgroundMinagawa, H., Gong, J., Jung, C., Watanabe, A., Lund‐Katz, S., Phillips, M. C., Saito, H., & Michikawa, M. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22073 · Cited by 90 · see citing works
Lefterov, I., Bookout, A., Wang, Z., Staufenbiel, M., Mangelsdorf, D., & Koldamova, R. (2007) · Molecular Neurodegeneration · doi:10.1186/1750-1326-2-20 · Cited by 89 · see citing works
Hirsch-Reinshagen, V., & Wellington, C. L. (2007) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32813aeabf · Cited by 61 · see citing works
Akram, A., Schmeidler, J., Katsel, P., Hof, P. R., & Haroutunian, V. (2010) · Brain Research · doi:10.1016/j.brainres.2010.01.006 · Cited by 50 · see citing works
MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease
Yoon, H., Flores, L. F., & Kim, J. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.04.020 · Cited by 23 · see citing works
“also demonstrated that ABCA1 as well as ABCG1 increased cholesterol efflux to APOE, leading to a reduction in Aβ generation [65].”
Background
- Authors
- Kim, W. S., Rahmanto, A. S., Kamili, A., Rye, K.-A., Guillemin, G. J., Gelissen, I. C., Jessup, W., Hill, A. F., & Garner, B.
- Affiliations
- Neuroscience Research Australia (AU)
- The Heart Research Institute (AU)
- St Vincent's Hospital Sydney (AU)
- UNSW Sydney (AU)
- The University of Melbourne (AU)
- Corresponding author
- Garner, Brett
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 282
- Issue
- 5
- Pages
- 2851-2861
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2105761603
- Cited by
- 191
- References
- 12
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 9 · 2023: 4 · 2022: 8 · 2021: 7 · 2020: 12 · 2019: 8 · 2018: 6 · 2017: 11 · 2016: 7 · 2015: 11 · 2014: 6 · 2013: 12 · 2012: 14
- FWCI
- 11.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Victoria University Research Repository (Victoria University) (submittedVersion, cc-by)
- Research Online (University of Wollongong) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- Medical Research Council
- National Health and Medical Research Council (222722, 350810)
- 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
- ABCG1, ABCA1, ABCA2, ABC transporters, amyloid-beta production, APP processing, cholesterol efflux, 24S-hydroxycholesterol, neuroblastoma cells, Alzheimer's disease
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 1, Animals, Apolipoproteins E, Brain, Cell Line, Cells, Cultured, Cholesterol, Cricetulus, Cricetinae, Humans, Kinetics, Male, Neurons, Recombinant Proteins, Transfection, Polymerase Chain Reaction, CHO Cells, ATP-Binding Cassette Transporters, Foreskin, ATP Binding Cassette Transporter 1
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