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. 2014 Jun 3;9:20.
doi: 10.1186/1750-1326-9-20.

Altered Microglial Response to Aβ Plaques in APPPS1-21 Mice Heterozygous for TREM2

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Free PMC article

Altered Microglial Response to Aβ Plaques in APPPS1-21 Mice Heterozygous for TREM2

Jason D Ulrich et al. Mol Neurodegener. .
Free PMC article

Abstract

Background: Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer's disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer's disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer's disease, we tested whether loss of one functional trem2 allele would affect Aβ plaque deposition or the microglial response to Aβ pathology in APPPS1-21 mice.

Results: There was no significant difference in Aβ deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2+/- vs. TREM2+/+ mice.

Conclusions: Loss of a single copy of trem2 had no effect on Aβ pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aβ deposition but that a 50% decrease inTREM2 expression does not affect Aβ plaque burden.

Figures

Figure 1
Figure 1
TREM2 heterozygosity does not affect Aβ plaque deposition in 3-month old APPPS1-21 mice. (A-D) Representative coronal brain sections from 3-month old from male TREM2 WT (A), male TREM2 Het (B), female TREM2 WT (C) and female TREM2 Het (D). Sections were immunostained with a biotinylated anti-Aβ antibody HJ3.4. (E) Quantification of the percentage of cortical area occupied by Aβ immunostaining. Two-way ANOVA analysis found a significant effect of gender (F1,39 = 13.63, p = 0.0007), but not genotype (F1,39 = 0.25, p = 0.62). (F) Quantification of the percentage of cortical area occupied by X-34 staining. Two-way ANOVA analysis found a significant effect of gender (F1,39 = 14.33, p = 0.0005), but not genotype (F1,39 = 0.08, p = 0.78; TREM2 WT (male, n = 12; female, n = 12) TREM2 Het (male, n = 9; female, n = 10)). Data are presented as mean ± SEM.
Figure 2
Figure 2
TREM2 heterozygosity does not affect PBS-insoluble Aβ levels in 3-month old APPPS1-21 mice. (A) Mean concentrations of PBS-insoluble Aβ40 in cortical tissue from TREM2 WT (male, n = 13; female, n = 12) and TREM2 Het (male, n = 8; female n = 10) mice were determined by ELISA. Two-way ANOVA analysis found a significant effect of gender (F1,38 = 5.49, p = 0.02), but not genotype (F1,38 = 0.55, p = 0.46). (B) Mean concentrations of PBS-insoluble Aβ42 in cortical tissue from TREM2 WT (male, n = 13; female, n = 12) and TREM2 Het (male, n = 8; female n = 10) mice were determined by ELISA. Two-way ANOVA analysis found a significant effect of gender (F1,38 = 5.96, p = 0.02), but not genotype (F1,38 = 0.07, p = 0.79). Data are presented as mean ± SEM.
Figure 3
Figure 3
Decreased plaque-associated microglia in TREM2 Het mice. (A-F) Representative images of Alexa568-HJ3.4-stained plaque and GFP-expressing microglia from TREM2 WT (A-C) and TREM2 Het (D-F) mice. (G) The number of microglia per 100 μm2 within a 20 μm2 radius of an Aβ plaque in TREM2 WT mice (25.1 ± 2.25, n = 10) and TREM2 Het mice (18.3 ± 1.24, n = 9) was compared using a Mann–Whitney test (p = 0.03). (H) The mean soma size off plaque-associated microglia in TREM2 WT mice (45.0 ± 2.23 μm2, n = 10) and TREM2 Het mice (37.9 ± 1.57 μm2, n = 9) was compared using a Mann–Whitney test (p = 0.03). (I) The percent area covered by plaque-associated microglia in TREM2 WT mice (14.1 ± 1.4%, n = 10) and TREM2 Het mice (8.8 ± 0.71%, n = 9) was compared using a Mann–Whitney test (p = 0.01).
Figure 4
Figure 4
TREM2 heterozygosity does not significantly affect the inflammatory milieu in 3-month old APPPS1-21 mice. (A) Quantification of relative gene expression of microglial markers and NOS2 in TREM2 WT and TREM2 Het mice (n = 4-6 mice/genotype). For each mRNA analyzed TREM2 Het values were normalized and compared to TREM2 WT values using a t-test followed by a Benjamini-Hochberg p-value correction for multiple comparisons. (B-D) Levels of inflammatory cytokines in cortical tissue from TREM2 WT (n = 6) and TREM2 Het (n = 6) mice were compared using a t-test followed by Benjamini-Hochberg p-value correction for multiple comparisons. Cytokine levels are plotted on different axis for clarity of presentation. All data are presented as mean ± SEM, *corrected p < 0.05.
Figure 5
Figure 5
TREM2 hemizygosity does not significantly affect Aβ plaque burden or expression of M1/M2 microglial markers in 7-month old APPPS1-21 mice. (A and B) Representative coronal brain sections from 7-month old female TREM2 WT (A) and TREM2 Het (B) mice. Sections were immunostained with the biotinylated anti-Aβ antibody, HJ3.4. (C) Quantification of the cortical area occupied by Aβ immunostaining. TREM2 WT (5.85 ± 0.69%, n = 9) and TREM2 Het (4.60 ± 0.66%, n = 7) were statistically compared using a Mann Whitney test (p = 0.25). (D) Quantification of microglial mRNA expression in TREM2 WT and TREM2 Het mice. For each mRNA examined TREM2 Het were normalized and compared to TREM2 WT mice using a t-test followed by Benamini-Hochberg p-value correction for multiple comparisons. All data are presented as mean ± SEM (n = 3-7 mice per group), *p < 0.05.

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