A dual role for apolipoprotein e in neuroinflammation: anti- and pro-inflammatory activity
Abstract
Chronically activated glia associated with amyloid plaques might contribute to neuronal dysfunction in Alzheimer's disease (AD) through generation of neuroinflammatory molecules. Apolipoprotein E (apoE), also found associated with amyloid plaques, has been hypothesized to serve an anti-inflammatory role in the CNS through its ability to modulate beta-amyloid (Abeta)-induced glial activation. To further characterize the effect of apoE on inflammation, we examined the ability of exogenously added human apoE3 and apoE4 to modulate neuro inflammatory responses of cultured rat glia. Apolipoprotein E3 (apoE3) and apoE4 suppressed oligomeric Abeta-induced production of inducible nitric oxide synthase and cyclo-oxygenase-2, supporting an anti- inflammatory role for apoE. Exogenous apoE also inhibited Abeta-induced production of endogenous apoE. However, exogenous apoE in the absence of Abeta stimulated production of the pro-inflammatory cytokine interleukin-1beta in an isoform-dependent manner, with apoE4 inducing a significantly greater response than apoE3. These data support the idea that Abeta stimulation of glial apoE limits neuroinflammation but that overproduction of apoE by activated glia might exacerbate inflammation. In addition, the observation that apoE4 has more robust pro-inflammatory activity than apoE3 provides a mechanistic link between the APOE4 allele and AD, and suggests potential apoE-based therapeutic strategies.
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Exogenously applied apoE4 has more robust pro-inflammatory activity than apoE3 in astrocytes and microglial cells.
“In support of this hypothesis, several studies demonstrated that exogenously applied apoE4 has more robust pro-inflammatory activity than apoE3 in astrocytes and microglial cells (Barger and Harmon, 1997; Guo et al., 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Guo et al., 2004
Increased levels of apoE limit Aβ-driven neuroinflammation, possibly functioning as a feedback mechanism.
“and the increased levels of apoE limit Aβ-driven neuroinflammation, possibly functioning as a feedback mechanism (Guo et al., 2004; LaDu et al., 2001).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Guo et al., 2004
Aβ induces the production of apoE.
“Interestingly, Aβ induces the production of apoE and the increased levels of apoE limit Aβ-driven neuroinflammation, possibly functioning as a feedback mechanism (Guo et al., 2004; LaDu et al., 2001).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Guo et al., 2004
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- Authors
- Guo, L., LaDu, M. J., & Van Eldik, L. J.
- Affiliations
- Northwestern University (US)
- Venue
- Journal of Molecular Neuroscience
- Published
- 2004
- Volume
- 23
- Issue
- 3
- Pages
- 205-212
- ISSN
- 0895-8696 (ISSN-L)
- OpenAlex
- W2316785311
- Cited by
- 175
- References
- 3
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 8 · 2023: 5 · 2022: 15 · 2021: 10 · 2020: 14 · 2019: 6 · 2018: 6 · 2017: 4 · 2016: 10 · 2015: 13 · 2014: 11 · 2013: 8 · 2012: 9
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG13939, AG 21184, P01AG021184)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- apolipoprotein E, APOE ε4, APOE3, neuroinflammation, Alzheimer's disease, amyloid-beta, glial activation, inducible nitric oxide synthase, cyclooxygenase-2, IL-1β, anti-inflammatory activity, pro-inflammatory activity, amyloid plaques
- MeSH terms
- Alzheimer Disease, Animals, Animals, Newborn, Apolipoproteins E, Astrocytes, Cerebral Cortex, Inflammation, Models, Neurological, Nervous System Diseases, Neuroglia, Peptide Fragments, Amyloid beta-Peptides, Rats, Sprague-Dawley, Cell Culture Techniques, Protein Isoforms, Rats, Apolipoprotein E3, Apolipoprotein E4
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