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Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype.

Minter MR, Moore Z, Zhang M, Brody KM, Jones NC, Shultz SR, Taylor JM, Crack PJ - Acta Neuropathol Commun (2016)

Bottom Line: A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood.These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aβ1-42 treatment of IFNAR1(-/-) primary glial cultures.Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne, 3010, Victoria, Australia.

ABSTRACT
A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood. Type-1 interferons (IFNs) are master regulators of innate immunity and have been implicated in multiple CNS disorders, however their role in AD progression has not yet been fully investigated. Hence, we generated APPSWE/PS1ΔE9 mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APPSWE/PS1ΔE9 x IFNAR1(-/-)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APPSWE/PS1ΔE9 x IFNAR1(-/-) mice displayed a modest reduction in Aβ monomer levels, despite maintenance of plaque deposition. This finding correlated with partial rescue of spatial learning and memory impairments in the Morris water maze in comparison to APPSWE/PS1ΔE9 mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice compared to APPSWE/PS1ΔE9 mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice in comparison to APPSWE/PS1ΔE9 mice. These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aβ1-42 treatment of IFNAR1(-/-) primary glial cultures. Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.

No MeSH data available.


Related in: MedlinePlus

Removal of IFNAR1 in APPSWE/PS1ΔE9 mice shifts the microglial phenotype to an anti-inflammatory state. a Q-PCR of cortical tissue isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls analyzing iNOS, CD11b, CD32 and CD33 pro-inflammatory glial marker expression levels. b Q-PCR of cortical tissue isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls analyzing TGFβ, YM1, ARG1, CD206, CCL22 and TREM2 anti-inflammatory glial marker expression levels. c Immunoblot of Tris–HCl soluble cortical protein lysates isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice using anti-SOCS-3. Comparative summaries of d Pro-inflammatory and e anti-inflammatory glial marker expression in APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice are displayed. For Q-PCR, all samples were normalized back to the Ct value of the housekeeping gene GAPDH (ΔCt). The mRNA of the variant genotype groups were then expressed relative to their gene-specific wildtype littermate controls. For western blotting, immunodetection of β-actin was used to ascertain loading quantities. Data are displayed as mean alone or as box plots described in the statistical analysis section in Materials and Methods (n = 9 per genotype; •represents outlier value; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). See Additional file 2: Table S1 for further analysis
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Fig5: Removal of IFNAR1 in APPSWE/PS1ΔE9 mice shifts the microglial phenotype to an anti-inflammatory state. a Q-PCR of cortical tissue isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls analyzing iNOS, CD11b, CD32 and CD33 pro-inflammatory glial marker expression levels. b Q-PCR of cortical tissue isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls analyzing TGFβ, YM1, ARG1, CD206, CCL22 and TREM2 anti-inflammatory glial marker expression levels. c Immunoblot of Tris–HCl soluble cortical protein lysates isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice using anti-SOCS-3. Comparative summaries of d Pro-inflammatory and e anti-inflammatory glial marker expression in APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice are displayed. For Q-PCR, all samples were normalized back to the Ct value of the housekeeping gene GAPDH (ΔCt). The mRNA of the variant genotype groups were then expressed relative to their gene-specific wildtype littermate controls. For western blotting, immunodetection of β-actin was used to ascertain loading quantities. Data are displayed as mean alone or as box plots described in the statistical analysis section in Materials and Methods (n = 9 per genotype; •represents outlier value; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). See Additional file 2: Table S1 for further analysis

Mentions: Elevation of iNOS pro-inflammatory marker expression was confirmed in APPSWE/PS1ΔE9 mice compared to wildtype mice (Wildtype: 1.1 ± 0.1-fold vs. APPSWE/PS1ΔE9: 2.6 ± 0.4-fold, p < 0.0001, n = 9 per genotype, Fig. 5a). Significantly, iNOS expression was decreased in APPSWE/PS1ΔE9 x IFNAR1−/− mice compared to APPSWE/PS1ΔE9 mice alone (APPSWE/PS1ΔE9: 2.6 ± 0.4-fold vs. APPSWE/PS1ΔE9 x IFNAR1−/−: 1.4 ± 0.1-fold, p = 0.0053, n = 9 per genotype, Fig. 5a). Transcript levels of the pro-inflammatory marker CD11b were elevated in APPSWE/PS1ΔE9 mice compared to wildtype mice (Wildtype: 1.0 ± 0.07-fold vs. APPSWE/PS1ΔE9: 2.4 ± 0.4-fold, p = 0.0014, n = 9 per genotype, Fig. 5a). Similar to the iNOS expression, CD11b transcript levels were decreased in APPSWE/PS1ΔE9 x IFNAR1−/− mice compared to APPSWE/PS1ΔE9 mice alone (APPSWE/PS1ΔE9: 2.4 ± 0.4-fold vs. APPSWE/PS1ΔE9 x IFNAR1−/−: 1.4 ± 0.1-fold, p = 0.0371, n = 9 per genotype, Fig. 5a). Expression of the CD32 pro-inflammatory marker was elevated in APPSWE/PS1ΔE9 mice compared to wildtype, however this elevation was not suppressed in APPSWE/PS1ΔE9 x IFNAR1−/− mice (Wildtype: 1.1 ± 0.1-fold vs. APPSWE/PS1ΔE9: 3.7 ± 0.6-fold, p < 0.0001, n = 9 per genotype, Fig. 5a). Indeed, CD32 levels in APPSWE/PS1ΔE9 x IFNAR1−/− mice were elevated compared to wildtype mice albeit not to the same levels as APPSWE/PS1ΔE9 mice (Wildtype: 1.1 ± 0.1-fold vs. APPSWE/PS1ΔE9 x IFNAR1−/−: 2.5 ± 0.3-fold, p = 0.0366, n = 9 per genotype, Fig. 5a). Expression of the CD33 pro-inflammatory marker was elevated in APPSWE/PS1ΔE9 mice compared to wildtype, but this elevation was not suppressed in APPSWE/PS1ΔE9 x IFNAR1−/− mice (Wildtype: 1.0 ± 0.05-fold vs. APPSWE/PS1ΔE9: 1.9 ± 0.3-fold, p = 0.0015, n = 9 per genotype, Fig. 5a).Fig. 5


Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype.

Minter MR, Moore Z, Zhang M, Brody KM, Jones NC, Shultz SR, Taylor JM, Crack PJ - Acta Neuropathol Commun (2016)

Removal of IFNAR1 in APPSWE/PS1ΔE9 mice shifts the microglial phenotype to an anti-inflammatory state. a Q-PCR of cortical tissue isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls analyzing iNOS, CD11b, CD32 and CD33 pro-inflammatory glial marker expression levels. b Q-PCR of cortical tissue isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls analyzing TGFβ, YM1, ARG1, CD206, CCL22 and TREM2 anti-inflammatory glial marker expression levels. c Immunoblot of Tris–HCl soluble cortical protein lysates isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice using anti-SOCS-3. Comparative summaries of d Pro-inflammatory and e anti-inflammatory glial marker expression in APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice are displayed. For Q-PCR, all samples were normalized back to the Ct value of the housekeeping gene GAPDH (ΔCt). The mRNA of the variant genotype groups were then expressed relative to their gene-specific wildtype littermate controls. For western blotting, immunodetection of β-actin was used to ascertain loading quantities. Data are displayed as mean alone or as box plots described in the statistical analysis section in Materials and Methods (n = 9 per genotype; •represents outlier value; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). See Additional file 2: Table S1 for further analysis
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Fig5: Removal of IFNAR1 in APPSWE/PS1ΔE9 mice shifts the microglial phenotype to an anti-inflammatory state. a Q-PCR of cortical tissue isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls analyzing iNOS, CD11b, CD32 and CD33 pro-inflammatory glial marker expression levels. b Q-PCR of cortical tissue isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls analyzing TGFβ, YM1, ARG1, CD206, CCL22 and TREM2 anti-inflammatory glial marker expression levels. c Immunoblot of Tris–HCl soluble cortical protein lysates isolated from 9 month old wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice using anti-SOCS-3. Comparative summaries of d Pro-inflammatory and e anti-inflammatory glial marker expression in APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice are displayed. For Q-PCR, all samples were normalized back to the Ct value of the housekeeping gene GAPDH (ΔCt). The mRNA of the variant genotype groups were then expressed relative to their gene-specific wildtype littermate controls. For western blotting, immunodetection of β-actin was used to ascertain loading quantities. Data are displayed as mean alone or as box plots described in the statistical analysis section in Materials and Methods (n = 9 per genotype; •represents outlier value; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). See Additional file 2: Table S1 for further analysis
Mentions: Elevation of iNOS pro-inflammatory marker expression was confirmed in APPSWE/PS1ΔE9 mice compared to wildtype mice (Wildtype: 1.1 ± 0.1-fold vs. APPSWE/PS1ΔE9: 2.6 ± 0.4-fold, p < 0.0001, n = 9 per genotype, Fig. 5a). Significantly, iNOS expression was decreased in APPSWE/PS1ΔE9 x IFNAR1−/− mice compared to APPSWE/PS1ΔE9 mice alone (APPSWE/PS1ΔE9: 2.6 ± 0.4-fold vs. APPSWE/PS1ΔE9 x IFNAR1−/−: 1.4 ± 0.1-fold, p = 0.0053, n = 9 per genotype, Fig. 5a). Transcript levels of the pro-inflammatory marker CD11b were elevated in APPSWE/PS1ΔE9 mice compared to wildtype mice (Wildtype: 1.0 ± 0.07-fold vs. APPSWE/PS1ΔE9: 2.4 ± 0.4-fold, p = 0.0014, n = 9 per genotype, Fig. 5a). Similar to the iNOS expression, CD11b transcript levels were decreased in APPSWE/PS1ΔE9 x IFNAR1−/− mice compared to APPSWE/PS1ΔE9 mice alone (APPSWE/PS1ΔE9: 2.4 ± 0.4-fold vs. APPSWE/PS1ΔE9 x IFNAR1−/−: 1.4 ± 0.1-fold, p = 0.0371, n = 9 per genotype, Fig. 5a). Expression of the CD32 pro-inflammatory marker was elevated in APPSWE/PS1ΔE9 mice compared to wildtype, however this elevation was not suppressed in APPSWE/PS1ΔE9 x IFNAR1−/− mice (Wildtype: 1.1 ± 0.1-fold vs. APPSWE/PS1ΔE9: 3.7 ± 0.6-fold, p < 0.0001, n = 9 per genotype, Fig. 5a). Indeed, CD32 levels in APPSWE/PS1ΔE9 x IFNAR1−/− mice were elevated compared to wildtype mice albeit not to the same levels as APPSWE/PS1ΔE9 mice (Wildtype: 1.1 ± 0.1-fold vs. APPSWE/PS1ΔE9 x IFNAR1−/−: 2.5 ± 0.3-fold, p = 0.0366, n = 9 per genotype, Fig. 5a). Expression of the CD33 pro-inflammatory marker was elevated in APPSWE/PS1ΔE9 mice compared to wildtype, but this elevation was not suppressed in APPSWE/PS1ΔE9 x IFNAR1−/− mice (Wildtype: 1.0 ± 0.05-fold vs. APPSWE/PS1ΔE9: 1.9 ± 0.3-fold, p = 0.0015, n = 9 per genotype, Fig. 5a).Fig. 5

Bottom Line: A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood.These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aβ1-42 treatment of IFNAR1(-/-) primary glial cultures.Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne, 3010, Victoria, Australia.

ABSTRACT
A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood. Type-1 interferons (IFNs) are master regulators of innate immunity and have been implicated in multiple CNS disorders, however their role in AD progression has not yet been fully investigated. Hence, we generated APPSWE/PS1ΔE9 mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APPSWE/PS1ΔE9 x IFNAR1(-/-)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APPSWE/PS1ΔE9 x IFNAR1(-/-) mice displayed a modest reduction in Aβ monomer levels, despite maintenance of plaque deposition. This finding correlated with partial rescue of spatial learning and memory impairments in the Morris water maze in comparison to APPSWE/PS1ΔE9 mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice compared to APPSWE/PS1ΔE9 mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice in comparison to APPSWE/PS1ΔE9 mice. These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aβ1-42 treatment of IFNAR1(-/-) primary glial cultures. Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.

No MeSH data available.


Related in: MedlinePlus