APOE genotype and sex affect microglial interactions with plaques in Alzheimer’s disease mice
Open accessAbstract
Microglia affect Alzheimer's disease (AD) pathogenesis in opposing manners, by protecting against amyloid accumulation in early phases of the disease and promoting neuropathology in advanced stages. Recent research has identified specific microglial interactions with amyloid plaques that exert important protective functions including attenuation of early pathology. It is unknown how these protective microglial interactions with plaques are affected by apolipoprotein E (APOE) genotype and sex, two well-established AD risk factors that modulate microglial function. We investigated this question using quantitative confocal microscopy to compare microglial interactions with amyloid plaques in male and female EFAD mice across APOE3 and APOE4 genotypes at 6 months of age. We observed that microglial coverage of plaques is highest in male APOE3 mice with significant reductions in coverage observed with both APOE4 genotype and female sex. Plaque compaction, a beneficial consequence of microglial interactions with plaques, showed a similar pattern in which APOE4 genotype and female sex were associated with significantly lower values. Within the plaque environment, microglial expression of triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial plaque coverage, was highest in male APOE3 mice and reduced by APOE4 genotype and female sex. These differences in plaque interactions were unrelated to the number of microglial processes in the plaque environment across groups. Interestingly, the pattern of amyloid burden across groups was opposite to that of microglial plaque coverage, with APOE4 genotype and female sex showing the highest amyloid levels. These findings suggest a possible mechanism by which microglia may contribute to the increased AD risk associated with APOE4 genotype and female sex.
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Reactive microglia migrate towards Aβ plaques, surround them and upregulate APOE, which binds to TREM2 and promotes plaque compaction.
“Reactive microglia migrate towards Aβ plaques, surround them and upregulate APOE, which binds to TREM2 and promotes plaque compaction154.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [154]
The Introduction says activated microglia associate with Aβ plaques, apoE is a TREM2 ligand, and TREM2-dependent microglial barriers help compact plaques. The Discussion links APOE loss with reduced microglial clustering and plaque compaction, but says the mechanism of APOE’s effect on plaque coverage is unclear. The paper does not establish that plaque-associated microglia upregulate APOE or that APOE binding to TREM2 directly promotes compaction; it also does not document migration toward plaques. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPrevious reports have demonstrated that gender can affect AD pathology, microglia response and APOE expression, while the protective and disease causing effects of APOE2 and APOE4 are variable in different ethnic populations.
“Previous reports have demonstrated that gender can affect AD pathology, microglia response and APOE expression (Stephen et al, 2019; Thomas et al, 2016; Sala Frigerio et al, 2019), while the protective and disease causing effects of APOE2 and APOE4 are variable in different ethnic populations (Farrer et al, 1997; Naslavsky et al, 2022).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Stephen et al, 2019
The Results report that sex was associated with amyloid plaque burden and microglial responses in EFAD mice. The Discussion also describes sex differences in microglial plaque interactions, but the paper does not establish that sex affects APOE expression. The statement about ethnic populations is attributed to other citations, not Stephen et al. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMicroglial coverage of amyloid plaques is highest in male APOE3 mice and reduced by female sex and APOE4 genotype.
“They discovered that microglial coverage of amyloid plaques is highest in male APOE3 mice and reduced by female sex and APOE4 genotype.”
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- Authors
- Stephen, T. L., Cacciottolo, M., Balu, D., Morgan, T. E., LaDu, M. J., Finch, C. E., & Pike, C. J.
- Affiliations
- University of Southern California (US)
- University of Illinois Chicago (US)
- Corresponding author
- Pike, C. J.
- Venue
- Acta Neuropathologica Communications
- Published
- 2019-05-21
- Volume
- 7
- Issue
- 1
- Pages
- 82-82
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC6528326
- OpenAlex
- W2946924931
- Cited by
- 115
- References
- 65
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 30 · 2023: 13 · 2022: 15 · 2021: 17 · 2020: 14 · 2019: 4
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (AG058068)
- Cure Alzheimer's Fund
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, microglia, amyloid plaques, apolipoprotein E, APOE ε4, APOE3, sex differences, TREM2, amyloid burden, neuroprotection
- MeSH terms
- Alzheimer Disease, Animals, Brain, Female, Genotype, Male, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Sex Characteristics, Microglia, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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