APOE genotype-specific differences in the innate immune response
Open accessAbstract
Apolipoprotein-E protein is an endogenous immunomodulatory agent that affects both the innate and the adaptive immune responses. Since individuals with the APOE4 gene demonstrate worsened pathology and poorer outcomes in many neurological disorders, we examined isoform-specific differences in the response of microglia, the primary cellular component of the brain's innate immune response, in detail. Our data demonstrate that microglia derived from APOE4/4 targeted replacement mice demonstrate a pro-inflammatory phenotype that includes altered cell morphology, increased NO production associated with increased NOS2 mRNA levels, and higher pro-inflammatory cytokine production (TNFalpha, IL-6, IL12p40) compared to microglia derived from APOE3/3 targeted replacement mice. The effect is gene dose-dependent and increases with the number of APOE4 gene alleles. The APOE genotype-specific immune profile observed in the microglial immune response is also observed in the cortex of aged APOE3/3 and APOE4/4 mice treated with lipopolysacchride (LPS) and in peripheral (peritoneal) macrophages. To determine if APOE4's action resulted from an isoform-specific difference in effective levels of the apolipoproteins, we generated mice expressing only a single allele of APOE3. Immune-stimulated macrophages from APOE3/0 mice demonstrated an increased inflammatory response compared to APOE3/3 mice, but less than in APOE4/4 mice. These data suggest that inhibition of inflammation depends upon the dose of apoE3 protein available and that apoE4 protein may alter inflammation partly by dose effects and partly by being qualitatively different than apoE3. Overall, these data emphasize the important role of apolipoprotein E and of the APOE genotype on the immune responses that are evident in most, if not all, neurological disease.
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Several in vivo studies of E4 mice and humans show an exaggerated response to inflammation in E4 individuals.
“several in vivo studies of E4 mice and humans show an exaggerated response to inflammation in E4 individuals (Vitek et al., 2009; Shi et al., 2017; Zhu et al., 2012; Gale et al., 2014).”
From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Vitek et al., 2009
The Discussion reports that LPS-injected APOE4/4 mice had greater increases in pro-inflammatory cytokine mRNA than APOE3/3 mice, and the Introduction cites other in vivo mouse studies with similar findings. Our copy discusses APOE4-associated human disease outcomes but does not report in vivo studies showing an exaggerated inflammatory response in humans. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPOE4 has been reported to impair TLR4 trafficking and downstream signaling in myeloid cells.
“APOE4 has been reported to impair TLR4 trafficking and downstream signaling in myeloid cells (Vitek et al., 2009; Liu et al., 2023)”
From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Vitek et al., 2009
The Discussion (page not provided) reports altered NF-κB and p38 MAP kinase signaling in APOE4-expressing immune cells, so it supports an effect on signaling. It does not describe impaired TLR4 trafficking or establish impaired TLR4-specific downstream signaling; the NF-κB activity it discusses is increased, not decreased. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA greater immune response associated with the ε4 allele is also observed in human APOE-TR mice and in cultured microglia/macrophages upon LPS stimulation.
“A greater immune response associated with the ε4 allele is also observed in human ApoE-targeted replacement (APOE-TR) mice [G] and in cultured microglia/macrophages upon LPS stimulation108–110.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [109]
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Pankiewicz, J. E., Lizińczyk, A. M., Franco, L. A., Diaz, J. R., Martá-Ariza, M., & Sadowski, M. J. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01261-z · Cited by 15 · see citing works
- Authors
- Vitek, M. P., Brown, C. M., & Colton, C. A.
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- Colton, Carol A.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 30
- Issue
- 9
- Pages
- 1350-1360
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC2782461
- OpenAlex
- W2096142564
- Cited by
- 362
- References
- 49
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 24 · 2023: 28 · 2022: 27 · 2021: 33 · 2020: 28 · 2019: 12 · 2018: 16 · 2017: 14 · 2016: 11 · 2015: 15 · 2014: 21 · 2013: 17 · 2012: 23
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (RF1AG057895, P50AG005128, AG019780, R01AG023802, R01AG019740, R01AG019780, AG023802-01)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- apolipoprotein E, APOE ε4, APOE3, microglia, innate immune response, neuroinflammation, gene dosage, pro-inflammatory phenotype, nitric oxide, NOS2, TNF-α, interleukin-6, IL-12, macrophages, lipopolysaccharide, targeted replacement mice
- MeSH terms
- Animals, Animals, Newborn, Apolipoproteins E, Cells, Cultured, Cerebral Cortex, Encephalitis, Genotype, Humans, Immunity, Innate, Mice, Transgenic, RNA, Messenger, Cytokines, Microglia, Mice, Knockout, Gene Dosage, Mice, Nitric Oxide Synthase Type II, Apolipoprotein E3, Apolipoprotein E4
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