Small molecule inducers of ABCA1 and apoE that act through indirect activation of the LXR pathway
Open accessAbstract
apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. However, direct synthetic LXR ligands have hepatotoxic side effects that limit their clinical use. Here, we describe a set of small molecules, previously annotated as antagonists of the purinergic receptor, P2X7, which enhance ABCA1 expression and activity as well as apoE secretion, and are not direct LXR ligands. Furthermore, P2X7 is not required for these molecules to induce ABCA1 upregulation and apoE secretion, demonstrating that the ABCA1 and apoE effects are mechanistically independent of P2X7 inhibition. Hence, we have identified novel dual activity compounds that upregulate ABCA1 across multiple CNS cell types, including human astrocytes, pericytes, and microglia, through an indirect LXR mechanism and that also independently inhibit P2X7 receptor activity.
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ABCA1 is vital in facilitating cholesterol efflux and is upregulated in a positive feedback loop via LXR, or LXR-independent cholesterol efflux, as well as APOE lipidation and production of cholesterol-rich HDL particles.
“This protein is vital in facilitating cholesterol efflux and is upregulated in a positive feedback loop via liver X receptor (LXR), or LXR-independent cholesterol efflux, as well as APOE lipidation and production of cholesterol-rich high-density lipoprotein (HDL) particles (Fan et al., 2018).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Fan et al., 2018
The Introduction (p. 830) describes ABCA1-mediated cholesterol efflux and apoE lipidation, and p. 831 says LXR regulates ABCA1. But the paper does not describe a positive-feedback loop or establish production of cholesterol-rich HDL particles; its Results (p. 834) examine apoE-containing lipoproteins. The Discussion (p. 840) says the tested compounds require LXR activity to induce ABCA1 and apoE, despite not binding LXR directly, so their effects do not establish LXR-independent efflux. (LLM, conf=0.90)
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Cites
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C. L., Bales, K. R., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33622 · Cited by 370 · cited 1× · see citing works
“ABCA1 increases CNS apoE lipidation and markedly decreases amyloid deposition (6).”
BackgroundSelf-citationHirsch-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
Self-citationATP-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 · cited 1× · 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).”
BackgroundmicroRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain
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Apolipoprotein E as a β-amyloid-independent factor in Alzheimer’s disease
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de Leeuw, S. M., Kirschner, A. W. T., Lindner, K., Rust, R., Budny, V., Wolski, W. E., Gavin, A.-C., Nitsch, R. M., & Tackenberg, C. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.11.007 · Cited by 105 · see citing works
Rasmussen, K. L., Tybjærg-Hansen, A., Nordestgaard, B. G., & Frikke-Schmidt, R. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz402 · Cited by 86 · see citing works
Direct and indirect effects of lipids on microglia function
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- Authors
- Fan, J., Zhao, R. Q., Parro, C., Zhao, W., Chou, H.-Y., Robert, J., Deeb, T. Z., Raynoschek, C., Barichievy, S., Engkvist, O., Maresca, M., Hicks, R., Meuller, J., Moss, S. J., Brandon, N. J., Wood, M. W., Kulic, I., & Wellington, C. L.
- Affiliations
- University of British Columbia (CA)
- AstraZeneca (Sweden) (SE)
- Tufts University (US)
- AstraZeneca (United States) (US)
- Corresponding author
- Wellington, Cheryl L.
- ORCID
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2018
- Volume
- 59
- Issue
- 5
- Pages
- 830-842
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC5928439
- OpenAlex
- W2794070712
- Cited by
- 50
- References
- 6
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 9 · 2018: 1
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-05-01)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Weston Brain Institute Rapid Response Grant (RR150031)
- 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, apolipoprotein E, liver X receptor, P2X7 receptor, small molecule inducers, Alzheimer's disease, astrocytes, pericytes, microglia, amyloid burden, purinergic signaling
- MeSH terms
- Benzenesulfonamides, Adamantane, Animals, Apolipoproteins E, Aziridines, Benzamides, Cells, Cultured, Humans, Naphthoquinones, Sulfonamides, Molecular Structure, Up-Regulation, Mice, Knockout, Mice, Small Molecule Libraries, Receptors, Purinergic P2X7, Purinergic P2X Receptor Antagonists, ATP Binding Cassette Transporter 1
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