Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells
Open accessAbstract
Although apolipoprotein (apo) E is synthesized in the brain primarily by astrocytes, neurons in the central nervous system express apoE, albeit at lower levels than astrocytes, in response to various physiological and pathological conditions, including excitotoxic stress. To investigate how apoE expression is regulated in neurons, we transfected Neuro-2a cells with a 17-kilobase human apoE genomic DNA construct encoding apoE3 or apoE4 along with upstream and downstream regulatory elements. The baseline expression of apoE was low. However, conditioned medium from an astrocytic cell line (C6) or from apoE-null mouse primary astrocytes increased the expression of both isoforms by 3-4-fold at the mRNA level and by 4-10-fold at the protein level. These findings suggest that astrocytes secrete a factor or factors that regulate apoE expression in neuronal cells. The increased expression of apoE was almost completely abolished by incubating neurons with U0126, an inhibitor of extracellular signal-regulated kinase (Erk), suggesting that the Erk pathway controls astroglial regulation of apoE expression in neuronal cells. Human neuronal precursor NT2/D1 cells expressed apoE constitutively; however, after treatment of these cells with retinoic acid to induce differentiation, apoE expression diminished. Cultured mouse primary cortical and hippocampal neurons also expressed low levels of apoE. Astrocyte-conditioned medium rapidly up-regulated apoE expression in fully differentiated NT2 neurons and in cultured mouse primary cortical and hippocampal neurons. Thus, neuronal expression of apoE is regulated by a diffusible factor or factors released from astrocytes, and this regulation depends on the activity of the Erk kinase pathway in neurons.
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Astrocytes secrete approx. 50-60% of the APOE they produce, while neurons retain most APOE intracellularly and only secrete approx. 10%.
“Astrocytes secrete approx. 50–60% of the APOE they produce, while neurons retain most APOE intracellularly and only secrete approx. 10% [5,6]”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [6]
The passage accompanying Fig. 6 reports that approximately 10% of apoE produced by mouse primary cortical neurons was secreted during 24 hours, supporting the neuronal part of the claim. It reports that more than 60% of apoE produced by mouse primary astrocytes was secreted, rather than approximately 50–60%. The measurements are from cultured mouse cells. (LLM, conf=0.88)
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- Authors
- Harris, F. M., Tesseur, I., Brecht, W. J., Xu, Q., Mullendorff, K., Chang, S., Wyss-Coray, T., Mahley, R. W., & Huang, Y.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Huang, Yadong
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-01
- Volume
- 279
- Issue
- 5
- Pages
- 3862-3868
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1980362319
- Cited by
- 135
- References
- 11
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 4 · 2016: 9 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 8
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG‐022074)
- National Institute on Aging (P01AG022074)
- National Heart, Lung, and Blood Institute (R01HL037063)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- apolipoprotein E, astrocytes, astrocyte-neuron communication, extracellular signal-regulated kinase, ERK signaling, astrocyte-conditioned medium
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Butadienes, Cells, Cultured, Enzyme Inhibitors, Gene Expression Regulation, Hippocampus, Humans, Immunohistochemistry, Models, Biological, Models, Genetic, Neuroglia, Neurons, Nitriles, RNA, Messenger, Blotting, Western, Up-Regulation, Culture Media, Conditioned, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Mice
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