Two Distal Downstream Enhancers Direct Expression of the Human Apolipoprotein E Gene to Astrocytes in the Brain
Open accessAbstract
Two distal downstream enhancers controlling astrocyte expression of the human apolipoprotein E (apoE) gene in the brain were identified by analysis of transgenic mice generated with various constructs of the apoE/C-I/C-IV/C-II gene cluster. In wild-type mice, the highest overall levels of apoE mRNA were found in astrocytes in the glomerular layer of olfactory bulbs and in Bergmann glia in the cerebellum. This pattern of expression was reproduced in transgenic mice expressing the entire human apoE gene cluster and also in transgenic mice expressing specific enhancer segments within the cluster. Expression of the human apoE transgene at these sites was specified by two enhancer domains: one enhancer is located 3.3 kb downstream of the apoE gene, and a duplication of this sequence is located 15 kb downstream of the apoE gene. Astrocyte enhancer activity was contained within 620 and 619 bp segments of these domains that show subtle differences in regional expression. In the absence of these distal enhancers, the apoE gene was not expressed in astrocytes. The relatively high levels of apoE expression at specific sites in the olfactory bulb and cerebellum suggest the presence of unique regulatory signals at these locations that may reflect common cellular properties and apoE gene functions. The localization of the two astrocytic enhancers reveals an unexpected complexity in the control of apoE production that is essential to understanding apoE function in the brain.
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Non-neuronal cells, mainly astrocytes and to some extent microglia, are the major cell types that express apoE in the brain.
“Non-neuronal cells, mainly astrocytes and to some extent microglia, are the major cell types that express apoE in the brain (Grehan et al., 2001; Pitas et al., 1987).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Grehan et al., 2001
The Discussion (page unavailable) says astrocytes account for a majority of brain apoE expression in the absence of inflammatory signals. The cited paper does not establish the claim that microglia also express apoE to a lesser extent. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAstrocytes are the primary source of apoE in the brain.
“Astrocytes are the primary source of apoE in the brain [23, 24].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [23]
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“Astrocytes and microglia are the major sources of APOE expression in the brain, but neurons also produce APOE under certain conditions [43, 44].”
Background
- Authors
- Grehan, S., Tse, E., & Taylor, J. M.
- Affiliations
- Gladstone Institutes (US)
- ORCID
- Taylor, John M.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-02-01
- Volume
- 21
- Issue
- 3
- Pages
- 812-822
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762321
- OpenAlex
- W2169359444
- Cited by
- 138
- References
- 62
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 9 · 2019: 6 · 2018: 4 · 2017: 10 · 2016: 9 · 2015: 3 · 2014: 5 · 2013: 8 · 2012: 6
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 37063, R01HL037063)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- apolipoprotein E, distal enhancers, astrocytes, gene expression regulation, transgenic mice, olfactory bulb, cerebellum, Bergmann glia
- MeSH terms
- Animals, Apolipoproteins E, Astrocytes, Brain, Cerebellum, Enhancer Elements, Genetic, Gene Expression Regulation, Multigene Family, Humans, Immunohistochemistry, Mice, Transgenic, Olfactory Bulb, Organ Specificity, Promoter Regions, Genetic, RNA, Messenger, Genes, Reporter, Transgenes, Mice
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