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Cited by 125Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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APOE genotype and sex affect microglial interactions with plaques in Alzheimer’s disease mice

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Stephen, T. L., Cacciottolo, M., Balu, D., Morgan, T. E., LaDu, M. J., Finch, C. E., Pike, C. J.·2019·Acta Neuropathologica Communications
DOI 10.1186/s40478-019-0729-zPMC PMC6528326
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Abstract

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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Fig. 1 Microglial plaque coverage in EFAD mice is diminished by APOE4 and female sex. a Representative images show ThioS-positive plaques (red) and Iba1-immunoreactive microglia (green) in the HPC of EFAD mice at 6 months of age. 3D images show composite, stacked images across the z-axis, whereas 2D images show individual z-sections with corresponding labeling across x- and y-axes. Scale bars = 5 μm. b Quantification of Iba1-immunoreactive processes in contact with ThioS-positive amyloid deposits (% plaque coverage) in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. c-d Correlation plots of plaque perimeter in relation to microglial plaque coverage in APOE3 (c) and APOE4 (d) male and female mice. Numbers of mice analyzed per group are as follows: male E3FAD (n = 6), female E3FAD (n = 5), male E4FAD (n = 5), and female E4FAD (n = 6). * denotes p < 0.05, ** denotes p < 0.01 *** denotes p < 0.001
Fig. 1 Microglial plaque coverage in EFAD mice is diminished by APOE4 and female sex. a Representative images show ThioS-positive plaques (red) and Iba1-immunoreactive microglia (green) in the HPC of EFAD mice at 6 months of age. 3D images show composite, stacked images across the z-axis, whereas 2D images show individual z-sections with corresponding labeling across x- and y-axes. Scale bars = 5 μm. b Quantification of Iba1-immunoreactive processes in contact with ThioS-positive amyloid deposits (% plaque coverage) in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. c-d Correlation plots of plaque perimeter in relation to microglial plaque coverage in APOE3 (c) and APOE4 (d) male and female mice. Numbers of mice analyzed per group are as follows: male E3FAD (n = 6), female E3FAD (n = 5), male E4FAD (n = 5), and female E4FAD (n = 6). * denotes p < 0.05, ** denotes p < 0.01 *** denotes p < 0.001CC BY · PubMed Central
Fig. 2 Effects of APOE genotype and sex on amyloid plaque dynamics. a Representative pseudo-colored images show relative circularity of ThioS-positive plaques, with intensity of labeling indicated by brightness (purple/black = low and yellow/white = high), across sex and APOE genotype. Scale bars = 5 μm. b Quantification of plaque circularity in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. Numbers of mice analyzed per group are as follows: male E3FAD (n = 6), female E3FAD (n = 5), male E4FAD (n = 5), and female E4FAD (n = 6). * denotes p < 0.05
Fig. 2 Effects of APOE genotype and sex on amyloid plaque dynamics. a Representative pseudo-colored images show relative circularity of ThioS-positive plaques, with intensity of labeling indicated by brightness (purple/black = low and yellow/white = high), across sex and APOE genotype. Scale bars = 5 μm. b Quantification of plaque circularity in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. Numbers of mice analyzed per group are as follows: male E3FAD (n = 6), female E3FAD (n = 5), male E4FAD (n = 5), and female E4FAD (n = 6). * denotes p < 0.05CC BY · PubMed Central
Fig. 3 Effects of APOE4 and sex on TREM2 expression levels near plaques. a Representative images showing ThioS-positive plaques (cyan) and Iba1-immunoreactive microglia (red) merged with TREM2 (green; with orange reflecting high co-localization with Iba1) in the HPC of EFAD mice. Scale bars = 10 μm. b Quantification of TREM2 load in the HPC in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. c TREM2 load in plaque negative regions (> 100 μm away). d TREM2 intensity in Iba1-immunoreactive microglia proximal to sites of microglia-plaque interaction (normalized to distal regions). Numbers of mice analyzed per group are as follows: (b-c) male E3FAD (n = 6), female E3FAD (n = 7), male E4FAD (n = 5), and female E4FAD (n = 6). d male E3FAD (n = 4), female E3FAD (n = 6), male E4FAD (n = 4), and female E4FAD (n = 5). *** denotes p < 0.001, **** denotes p < 0.0001
Fig. 3 Effects of APOE4 and sex on TREM2 expression levels near plaques. a Representative images showing ThioS-positive plaques (cyan) and Iba1-immunoreactive microglia (red) merged with TREM2 (green; with orange reflecting high co-localization with Iba1) in the HPC of EFAD mice. Scale bars = 10 μm. b Quantification of TREM2 load in the HPC in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. c TREM2 load in plaque negative regions (> 100 μm away). d TREM2 intensity in Iba1-immunoreactive microglia proximal to sites of microglia-plaque interaction (normalized to distal regions). Numbers of mice analyzed per group are as follows: (b-c) male E3FAD (n = 6), female E3FAD (n = 7), male E4FAD (n = 5), and female E4FAD (n = 6). d male E3FAD (n = 4), female E3FAD (n = 6), male E4FAD (n = 4), and female E4FAD (n = 5). *** denotes p < 0.001, **** denotes p < 0.0001CC BY · PubMed Central
Fig. 4 Effects of APOE genotype and sex on numbers of microglial processes. a Representative image of a thresholded confocal stack labeled with ThioS (cyan outline) and Iba1 immunoreactive microglia (black) in the HPC. The image below shows an overlay with Sholl analysis grid. b Microglial process number within 20 μm of ThioS-labeled plaques in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. c Microglial process number/cell within 20 μm of ThioS-labeled plaques. d Quantification of microglial process intersections at increasing distances from ThioS-labeled plaques in male (black lines) and female (red lines) EFAD mice with APOE3 (solid lines) and APOE4 (dashed lines) genotypes. Numbers of mice analyzed per group are as follows: male E3FAD (n = 6), female E3FAD (n = 5), male E4FAD (n = 4), and female E4FAD (n = 5). ns denotes not significant, * denotes p < 0.05, *** denotes p < 0.001
Fig. 4 Effects of APOE genotype and sex on numbers of microglial processes. a Representative image of a thresholded confocal stack labeled with ThioS (cyan outline) and Iba1 immunoreactive microglia (black) in the HPC. The image below shows an overlay with Sholl analysis grid. b Microglial process number within 20 μm of ThioS-labeled plaques in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. c Microglial process number/cell within 20 μm of ThioS-labeled plaques. d Quantification of microglial process intersections at increasing distances from ThioS-labeled plaques in male (black lines) and female (red lines) EFAD mice with APOE3 (solid lines) and APOE4 (dashed lines) genotypes. Numbers of mice analyzed per group are as follows: male E3FAD (n = 6), female E3FAD (n = 5), male E4FAD (n = 4), and female E4FAD (n = 5). ns denotes not significant, * denotes p < 0.05, *** denotes p < 0.001CC BY · PubMed Central
Fig. 5 Effects of APOE genotype and sex on AD-related pathology. a Representative images show ThioS-positive plaques (cyan) and Iba-1 immunoreactive microglia (white) in the HPC of EFAD mice. Scale bars = 15 μm. b Quantification of amyloid plaque load (% of total ROI area) in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. c-d Quantification of microglia load (% of total ROI area) near (< 100 μm, C) and far (> 100 μm, D) from ThioS-positive plaques. e-f Quantification of activated microglial phenotype (mean soma area of Iba1-immunoreactive cells) near (< 100 μm, E) and far (> 100 μm, F) from ThioS-positive plaques. Numbers of mice analyzed per group are as follows: male E3FAD (n = 7), female E3FAD (n = 7), male E4FAD (n = 5), and female E4FAD (n = 6). * denotes p < 0.05, ** denotes p < 0.01, **** denotes p < 0.0001, ns denotes not significant
Fig. 5 Effects of APOE genotype and sex on AD-related pathology. a Representative images show ThioS-positive plaques (cyan) and Iba-1 immunoreactive microglia (white) in the HPC of EFAD mice. Scale bars = 15 μm. b Quantification of amyloid plaque load (% of total ROI area) in male (M) and female (F) EFAD mice with APOE3 (open bars) and APOE4 (filled bars) genotypes. c-d Quantification of microglia load (% of total ROI area) near (< 100 μm, C) and far (> 100 μm, D) from ThioS-positive plaques. e-f Quantification of activated microglial phenotype (mean soma area of Iba1-immunoreactive cells) near (< 100 μm, E) and far (> 100 μm, F) from ThioS-positive plaques. Numbers of mice analyzed per group are as follows: male E3FAD (n = 7), female E3FAD (n = 7), male E4FAD (n = 5), and female E4FAD (n = 6). * denotes p < 0.05, ** denotes p < 0.01, **** denotes p < 0.0001, ns denotes not significantCC BY · PubMed Central

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Metadata

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.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2019-05-21
Volume
7
Issue
1
Pages
82-82
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-019-0729-z
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
Licence
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
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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

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