APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response
Open accessAbstract
Human apolipoprotein E is the major apolipoprotein expressed in the brain and exists as three isoforms, designated E2, E3, and E4. Although evidence suggests that apolipoprotein E plays an important role in modifying systemic and brain inflammatory responses, there is little data investigating apoE isoform-specific effects in vivo. In this study, we compared the inflammatory responses of targeted-replacement mice expressing the human APOE3 and APOE4 genes after intravenous administration of lipopolysaccharide. Animals expressing the E4 allele had significantly greater systemic and brain elevations of the pro-inflammatory cytokines TNFalpha and IL-6 as compared with their APOE3 counterparts, suggesting an isoform-specific effect of the immunomodulatory properties of apoE. Furthermore, intravenous administration of a small apoE-mimetic peptide derived from the receptor-binding region of the apoE holoprotein (apoE-(133-149)) similarly suppressed both systemic and brain inflammatory responses in mice after lipopolysaccharide administration. These results suggest that apoE plays an isoform-specific role in mediating the systemic and brain inflammatory responses. Moreover, because exogenous administration of this apoE mimetic peptide is effective at suppressing both systemic and brain inflammation, it may represent a novel therapeutic strategy for diseases characterized by systemic or central nervous system inflammation, such as septic shock, multiple sclerosis, and traumatic brain injury.
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APOE genotype influences the inflammatory response, with E4 expression linked to significantly higher cytokine levels in both humans and mice compared to E3 or E2.
“In addition to metabolic dysregulation, APOE genotype also influences the inflammatory response, with E4 expression linked to significantly higher cytokine levels in both humans and mice compared to E3 or E2”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Lynch et al., 2003
The Abstract and the section 'Effect of apoE Isoform on Inflammatory Response' report significantly higher TNFα and IL-6 levels in APOE4 mice than in APOE3 mice after LPS injection. The study did not compare cytokine levels with APOE2, and the Discussion describes the human evidence as preliminary rather than establishing significantly higher cytokine levels in humans. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIntravenous LPS administration results in elevated proinflammatory cytokines in E4 mice compared to E3 mice within three hours of injection.
“Similarly, intravenous LPS administration results in elevated proinflammatory cytokines in E4 mice compared to E3 mice within three hours of injection”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Lynch et al., 2003
After intravenous administration of LPS, apoE4 knock-in mice had greater inflammatory responses compared with apoE3 knock-in mice.
“After intravenous administration of LPS, apoE4 knock-in mice had greater inflammatory responses compared with apoE3 knock-in mice (Colton et al., 2004; Lynch et al., 2003).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Lynch et al., 2003
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- Authors
- Lynch, J. R., Tang, W., Wang, H., Vitek, M. P., Bennett, E. R., Sullivan, P. M., Warner, D. S., & Laskowitz, D. T.
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- Laskowitz, Daniel T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 278
- Issue
- 49
- Pages
- 48529-48533
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2058120050
- Cited by
- 394
- References
- 2
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 14 · 2023: 17 · 2022: 24 · 2021: 33 · 2020: 21 · 2019: 13 · 2018: 16 · 2017: 8 · 2016: 20 · 2015: 18 · 2014: 11 · 2013: 17 · 2012: 18
- FWCI
- 6.89
- 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
- National Institute on Aging (K08AG022230)
- National Institute of Neurological Disorders and Stroke (1R21 NS4487-01)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Keywords
- apolipoprotein E, APOE isoforms, APOE ε4, APOE3, lipopolysaccharide, neuroinflammation, systemic inflammation, TNF-α, interleukin-6, receptor-binding region, immunomodulation, septic shock, multiple sclerosis, traumatic brain injury
- MeSH terms
- Amino Acid Sequence, Animals, Apolipoproteins E, Central Nervous System, Genotype, Inflammation, Male, Mice, Inbred C57BL, Molecular Sequence Data, Peptides, RNA, Messenger, Tumor Necrosis Factor-alpha, Interleukin-6, Molecular Mimicry, Mice
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