Microglia-derived APOE2 improves remyelination even in the presence of endogenous APOE4
Open accessAbstract
Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement significantly improved remyelination, lessened microgliosis, and decreased astrocytic lipid droplet load following CPZ-remyelination. Our results indicate that microglia-specific E2 expression, in the presence of continued E4 expression, may provide protection against myelin loss via both cell-autonomous and non-autonomous immunometabolic mechanisms.
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E2 expression decreases lipid accumulation compared to E3 and E4.
“decrease lipid accumulation”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Nolt et al., 2025
The Results section, “Microglial APOE genotype modulates ApoE protein expression and lipid droplet distribution” (page unavailable), reports less astrocytic Plin2, a lipid-droplet marker, after remyelination in mice with microglial E2 replacement than in E4 controls. It found no significant difference in microglial Plin2 and did not test an E3 group, so it does not establish a general decrease in lipid accumulation compared with both E3 and E4. (LLM, conf=0.88)
Experimental — accuracy not yet measuredE2 expression decreases microgliosis compared to E3 and E4.
“decrease microgliosis”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Nolt et al., 2025
The Results section on short remyelination reports lower IBA1+ microglial reactivity in mice with microglial E2 expression than in E4 controls, specifically in the corpus callosum after remyelination. It does not report an E2-versus-E3 comparison; the Discussion instead describes another study finding less microgliosis in E4 mice than in E3 or E2 mice following demyelination. (LLM, conf=0.88)
Experimental — accuracy not yet measuredE2 expression increases phagocytic activity in microglia compared to E3 and E4.
“E2 expression has been shown to increase phagocytic activity”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Nolt et al., 2025
The Discussion reports that E4 microglia have reduced phagocytic activity compared with E2 and E3, supporting an E2-versus-E4 difference. It does not establish that E2 increases activity relative to E3. In this paper’s own demyelination experiments, switching microglia from E4 to E2 did not increase the measured phagocytic indicators (Results and Discussion; page unavailable). (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe APOE switch model allows for inducible and cell-specific replacement of E4 with E2 in microglia.
“Using our novel APOE “switch” model that allows for the inducible and cell-specific replacement of E4 with E2”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Nolt et al., 2025
The 4s2M mice express APOE4 in all cell types except microglia, which selectively transition to APOE2 expression upon tamoxifen injection.
“We generated APOE4s2flox/flox xTmem119-CreERT2 APOE switch mice (4s2M) that would express APOE4 in all cell types except microglia, which would selectively transition to APOE2 expression upon tamoxifen injection”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Nolt et al., 2025
E2 expression upregulates genes associated with cellular migration and the immune response in microglia compared to E3 and E4.
“upregulate genes associated with cellular migration and the immune response in microglia compared to E3 and E4”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Nolt et al., 2025
The Results section on microgliosis reports IBA1, CD68 and Trem2 measurements after switching microglia from E4 to E2, but not an E2-versus-E3-versus-E4 comparison of migration- or immune-response genes. Searches for “cellular migration” and “immune response genes E2 E3 E4” found no passage in our copy establishing the claimed upregulation; page numbers were not available. (LLM, conf=0.74)
Experimental — accuracy not yet measured
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Cited by
Sorted by citations
ApoE expression across the CNS: Who, What, Where, When, and How (much)?
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00028-x · Cited by 2 · see citing works
Self-citationNolt, G. L., MacLean, S. M., Golden, L. R., Thorpe, S. P., Stephens, I. O., Funnell, J. L., Brock, C. R., Lucido, C. C., Smith, L., Hernandez, G., et al. (2027) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2026.08.005
Self-citation
- Authors
- Nolt, G. L., Golden, L. R., Thorpe, S. P., Funnell, J. L., Stephens, I. O., Hernandez, G., MacLean, S. M., Lucido, C. C., Brock, C. R., Pallerla, A. V., Adreon, D. R., Williams, H. C., Morganti, J. M., & Johnson, L. A.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Johnson, Lance A.
- ORCID
- Venue
- Journal of Neuroinflammation
- Published
- 2025-12-11
- Volume
- 23
- Issue
- 1
- Pages
- 18-18
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC12802005
- OpenAlex
- W4417241593
- Cited by
- 5
- References
- 33
- Citations by year
- 2026: 5
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (T32 AG078110, RF1NS118558, R01AG081421)
- National Institute of General Medical Sciences (P20 GM148326)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- apolipoprotein E, APOE2, APOE ε4, microglia, remyelination, demyelination, cuprizone, lysophosphatidylcholine, microglial activation, astrocytes, lipid droplets, immunometabolism, multiple sclerosis, Alzheimer's disease
- MeSH terms
- Remyelination, Animals, Cuprizone, Demyelinating Diseases, Lysophosphatidylcholines, Male, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath, Microglia, Mice, Apolipoprotein E4, Apolipoprotein E2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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