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Cited by 25Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsCholesterol and Lipid Metabolism

Axl receptor tyrosine kinase is a regulator of apolipoprotein E

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Zhao, Wenchen, Fan, Jianjia, Kulic, Iva, Koh, Cheryl, Clark, Amanda, Meuller, Johan, Engkvist, Ola, Barichievy, Samantha +13 more·2020·Molecular Brain
DOI 10.1186/s13041-020-00609-1PMC PMC7197143
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Abstract

Alzheimer’s disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. AZ7235, a previously discovered Axl kinase inhibitor, was identified to have robust apoE activity in brain microglia, astrocytes and pericytes. AZ7235 also increased expression of ATP-binding cassette protein A1 (ABCA1), which is involved in the lipidation and secretion of apoE. Moreover, AZ7235 did not exhibit Liver-X-Receptor (LXR) activity and stimulated apoE and ABCA1 expression in the absence of LXR. Target validation studies using AXL−/− CCF-STTG1 cells showed that Axl is required to mediate AZ7235 upregulation of apoE and ABCA1. Intriguingly, apoE expression and secretion was significantly attenuated in AXL-deficient CCF-STTG1 cells and reconstitution of Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl also plays a role in maintaining apoE homeostasis in astrocytes independent of its kinase activity. Lastly, these effects may require human apoE regulatory sequences, as AZ7235 exhibited little stimulatory activity toward apoE and ABCA1 in primary murine glia derived from neonatal human APOE3 targeted-replacement mice. Collectively, we identified a small molecule that exhibits robust apoE and ABCA1 activity independent of the LXR pathway in human cells and elucidated a novel relationship between Axl and apoE homeostasis in human astrocytes.

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Authors
Zhao, W., Fan, J., Kulic, I., Koh, C., Clark, A., Meuller, J., Engkvist, O., Barichievy, S., Raynoschek, C., Hicks, R., Maresca, M., Wang, Q., Brown, D. G., Lok, A., Parro, C., Robert, J., Chou, H.-Y., Zuhl, A. M., Wood, M. W., Brandon, N. J., & Wellington, C. L.
Affiliations
  • University of British Columbia (CA)
  • AstraZeneca (United States) (US)
  • AstraZeneca (Sweden) (SE)
Corresponding author
Wellington, Cheryl L.
ORCID
Venue
Molecular Brain
Publisher
Springer Science and Business Media LLC
Published
2020-05-04
Volume
13
Issue
1
Pages
66-66
ISSN
1756-6606 (ISSN-L)
DOI
10.1186/s13041-020-00609-1
PMC
PMC7197143
OpenAlex
W3021609647
Cited by
25
References
16
Citations by year
2026: 5 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 5 · 2020: 2
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Brain (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • cIRcle (University of British Columbia) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open Collections
Funders
  • AstraZeneca
  • Weston Brain Institute (RR182016)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
AXL receptor tyrosine kinase, apolipoprotein E, apoE secretion, ABCA1, AXL kinase inhibitor, Alzheimer's disease, astrocytes, lipid modification, small molecule screening, microglia, pericytes
MeSH terms
Axl Receptor Tyrosine Kinase, Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Astrocytoma, Cell Survival, Humans, Proto-Oncogene Proteins, Microglia, Receptor Protein-Tyrosine Kinases, Cell Line, Tumor, Mice, Gene Knockdown Techniques, High-Throughput Screening Assays, ATP Binding Cassette Transporter 1

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