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1.
Figure 6

Figure 6. TNFα levels in peritoneal macrophages derived from ovariectomized APOE3 and APOE4 mice after replacement of endogenous estrogen. From: The APOE4 genotype alters the response of microglia and macrophages to 17?-estradiol.

Average supernatant levels of TNFα (±SEM) were measured in PIC+IFNγ or LPS+IFNγ-treated macrophages cultured from OVX or OVX + Est. Pellet mice. For treatment with LPS+IFNγ (A), a significant effect of genotype (p = 0.024) or of treatment was observed (p < 0.0001). No significant interaction was found. For treatment with PIC+IFNγ (B), a significant interaction between genotype and treatment was observed (p < 0.0001). # = p < 0.05 for APOE3 compared to APOE4; ## = p < 0.01 for APOE3 compared to APOE4; *** = p < 0.001 for OVX + pellet compared to OVX alone.

Candice M. Brown, et al. Neurobiol Aging. ;29(12):1783-1794.
2.
Figure 2

Figure 2. ICI 182,780 blocks 17β-estradiol in APOE3 microglia. From: The APOE4 genotype alters the response of microglia and macrophages to 17?-estradiol.

Microglia from APOE3 and APOE4 mice were pretreated with 17β-estradiol in the presence and absence of ICI 182,780 followed by the addition of LPS+ IFNγ. Average (±SEM) supernatant nitrite levels were determined and the effect of 17β-estradiol and ICI 182,780 treatment compared between APOE3 and APOE4 mice. Significance was determined using 2-way ANOVA with the Bonferroni post-hoc test. A significant interaction was observed between genotype and the response to treatment (p = 0.005); *** = p < 0.001 for treatments compared to LPS+ IFNγ alone.

Candice M. Brown, et al. Neurobiol Aging. ;29(12):1783-1794.
3.
Figure 5

Figure 5. Nitrite production in peritoneal macrophages derived from ovariectomized APOE3 and APOE4 mice after replacement of endogenous estrogen. From: The APOE4 genotype alters the response of microglia and macrophages to 17?-estradiol.

Peritoneal macrophages from ovariectomized (OVX) mice and OVX mice treated with a slow release estrogen pellet (OVX + Est Pellet) were immune activated with LPS+IFNγ (A) or PIC+IFNγ (B). Average (±SEM) supernatant nitrite concentrations were determined and significant differences were calculated using 2-way ANOVA with the Bonferroni post-hoc test. A significant interaction was observed between APOE genotype and the treatment condition for both types of immune induction (p < 0.0001). # = p < 0.05 for APOE3 compared to APOE4; ## = p < 0.01 for APOE3 compared to APOE4; * = p < 0.05 for OVX + Est pellet compared to OVX alone; *** = p < 0.001 for OVX + Est pellet compared to OVX alone.

Candice M. Brown, et al. Neurobiol Aging. ;29(12):1783-1794.
4.
Figure 4

Figure 4. Peritoneal macrophages from ovariectomized APOE4 mice also demonstrate decreased responsiveness to exogenous treatment with 17β-estradiol. From: The APOE4 genotype alters the response of microglia and macrophages to 17?-estradiol.

Cultured peritoneal macrophages from ovariectomized APOE3 or APOE4 mice were pretreated with 1nM 17β-estradiol followed by the addition of 100 ng/ml LPS plus 100 U/ml IFNγ (4A: LPS + IFNγ) or 50μg/ml PIC + 100 U/ml IFNγ (4B; PIC + IFNγ) in the continuing presence of 1 nM 17β-estradiol. Data are presented as the average supernatant nitrite levels (± SEM) and a 2-way ANOVA with the Bonferroni post-hoc test was used to determine significant differences. A significant interaction was observed between APOE genotype and the 17β-estradiol dose for either LPS + IFNγ or PIC + IFNγ-stimulated conditions (p < 0.0001). *** = p < 0.001 compared to LPS + IFNγ alone; # = p < 0.05 for APOE3 compared to APOE4; ## = p < 0.01 for APOE3 compared to APOE4.

Candice M. Brown, et al. Neurobiol Aging. ;29(12):1783-1794.
5.
Figure 1

Figure 1. APOE genotype influences the effect of 17β-estradiol on immune activated microglia. From: The APOE4 genotype alters the response of microglia and macrophages to 17?-estradiol.

Cultured microglia from either APOE3 or APOE4 mice were pretreated with varying doses of 17β-estradiol (0.1 to 5 nM) followed by the addition of 100U/ml IFNγ and 100 ng/ml LPS. A–C: Supernatant nitrite and cytokine levels were measured in the same cell supernatants collected from a single representative APOE3 or APOE4 litter group. Significance was determined using 2-way ANOVA with the Bonferroni post-hoc test. (A) Supernatant nitrite levels demonstrated a significant interaction between APOE genotype and 17β-estradiol dose; p = 0.022; ** = p < 0.01 for 1 nM 17β-estradiol compared to LPS+IFNγ alone in APOE 3 microglia; * = p < 0.05 for 1 or 5 nM 17β-estradiol compared to LPS+IFNγ alone for APOE4 microglia. (B) Supernatant TNFα levels demonstrated a significant effect of genotype (p = 0.0001) and of estrogen dose (p = 0.037). (C) Supernatant IL-6 levels demonstrated a significant effect of genotype (p = 0.0001). D–F: Data represent the average relative change (±SEM) from LPS+IFNγ alone (=1.0) for 6–12 different litter groups, 3 wells cultured per litter group. (D) The change in supernatant nitrite levels demonstrated a significant interaction between APOE genotype and estrogen response (p= 0.0134);* = p < 0.05 for APOE3 vs APOE4; *** = p < 0.001 for APOE3 vs APOE4 (E) The change in supernatant TNFα levels demonstrated a significant interaction between genotype and estrogen dose (p < 0.0001); ** = p < 0.01 for APOE3 vs APOE4; *** = p < 0.001 for APOE3 vs APOE4. (F) The change in supernatant IL-6 levels demonstrated a significant interaction between genotype and estrogen dose (p < 0.0005); *** = p < 0.001 for APOE3 vs APOE4.

Candice M. Brown, et al. Neurobiol Aging. ;29(12):1783-1794.
6.
Figure 3

Figure 3. Expression of mRNA and protein for ERα and ERβ in microglia from APOE3 and APOE4 mice. From: The APOE4 genotype alters the response of microglia and macrophages to 17?-estradiol.

(A and B) Quantitative RT-PCR was used to measure the average fold change (±SEM) in ERα and ERβ mRNA in microglia using untreated APOE3 as the calibrator. (A) Basal (untreated) levels of ERα mRNA were significantly higher in APOE4 microglia. Significance was determined using 2-way ANOVA with the Bonferroni post-hoc test. A significant effect of genotype was observed (p = 0.0025) for n = 7–12 cultures from a minimum of 3 different litter groups per genotype; ** = p < 0.01 for APOE4 compared to APOE3. (B) No significant difference was observed between untreated or treated APOE3 and APOE4 ERβ mRNA levels. A significant effect of LPS+IFNγ treatment compared to untreated was observed for both APOE3 and APOE4 mRNA (*** = p< 0.001). (C) ERα (top panel) and ERβ (middle and bottom panels) protein levels in untreated microglial lysates were determined using Western blot (labeled- Mg) from APOE3 (labeled- 3) and APOE4 (labeled- 4) mice. For ERβ, blots are presented from 3 different untreated microglial litter groups. Permanently transfected neuronal cells derived from the N2a cell line expressing human APOE3 (labeled -3) or human APOE4 (labeled -4) [6] were used as controls to demonstrate ER antibody specificity. N2a cells only express ERα and do not express ERβ. GADPH served as a loading control.

Candice M. Brown, et al. Neurobiol Aging. ;29(12):1783-1794.

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