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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

Aβ1-42 induces a pro-inflammatory phenotype in primary cultured glia with removal of IFNAR demonstrating a predmoninatly anti-inflammatory response. a Q-PCR of primary wildtype and IFNAR1−/− glial cultures treated with 10 μM Aβ1-42 for 24–96 h analyzing iNOS, CD11b and CD32 pro-inflammatory glial marker expression levels. b Q-PCR of primary wildtype and IFNAR1−/− glial cultures treated with 10 μM Aβ1-42 for 24–96 h analyzing ARG1, CCL22, YM1, CD206 and TGFβ anti-inflammatory glial marker expression levels. For Q-PCR all samples were normalized back to the Ct value of the housekeeping gene GAPDH (ΔCt). The mRNA of the Aβ1-42 treatment groups was then expressed relative to their gene-specific vehicle controls (fold change, ΔΔCt). Data are displayed as mean ± SEM (n = 4 (wildtype), n = 5 (IFNAR1−/−); *p < 0.05, **p < 0.01). See Additional file 2: Table S1 for further analysis
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Fig7: Aβ1-42 induces a pro-inflammatory phenotype in primary cultured glia with removal of IFNAR demonstrating a predmoninatly anti-inflammatory response. a Q-PCR of primary wildtype and IFNAR1−/− glial cultures treated with 10 μM Aβ1-42 for 24–96 h analyzing iNOS, CD11b and CD32 pro-inflammatory glial marker expression levels. b Q-PCR of primary wildtype and IFNAR1−/− glial cultures treated with 10 μM Aβ1-42 for 24–96 h analyzing ARG1, CCL22, YM1, CD206 and TGFβ anti-inflammatory glial marker expression levels. For Q-PCR all samples were normalized back to the Ct value of the housekeeping gene GAPDH (ΔCt). The mRNA of the Aβ1-42 treatment groups was then expressed relative to their gene-specific vehicle controls (fold change, ΔΔCt). Data are displayed as mean ± SEM (n = 4 (wildtype), n = 5 (IFNAR1−/−); *p < 0.05, **p < 0.01). See Additional file 2: Table S1 for further analysis

Mentions: Significantly, expression of the iNOS pro-inflammatory marker was elevated in wildtype but not IFNAR1−/− glial cultures in response to Aβ1-42 (24 h: Wildtype: 5.4 ± 2.8-fold vs. IFNAR1−/−: 1.1 ± 0.3-fold, p = 0.0195; 48 h: Wildtype: 5.9 ± 2.3-fold vs. IFNAR1−/−: 0.6 ± 0.06-fold, p = 0.0032, n = 4–5 per genotype, Fig. 7a). Transcript levels of the CD11b pro-inflammatory marker were also elevated in Aβ1-42-treated wildtype cultures but not when IFNAR1 was absent (72 h: Wildtype: 3.6 ± 0.9-fold vs. IFNAR1−/−: 0.7 ± 0.2-fold, p = 0.0274; 96 h: Wildtype: 4.1 ± 1.2-fold vs. IFNAR1−/−: 0.8 ± 0.2-fold, p = 0.0083, n = 4–5 per genotype, Fig. 7a). Expression levels of the CD32 pro-inflammatory marker were also reduced in IFNAR1−/− glial cultures when compared to wildtype counterparts upon Aβ1-42 insult (96 h: Wildtype: 4.6 ± 1.4-fold vs. IFNAR1−/−: 1.4 ± 0.2-fold, p = 0.0054, n = 4–5 per genotype, Fig. 7a).Fig. 7


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)

Aβ1-42 induces a pro-inflammatory phenotype in primary cultured glia with removal of IFNAR demonstrating a predmoninatly anti-inflammatory response. a Q-PCR of primary wildtype and IFNAR1−/− glial cultures treated with 10 μM Aβ1-42 for 24–96 h analyzing iNOS, CD11b and CD32 pro-inflammatory glial marker expression levels. b Q-PCR of primary wildtype and IFNAR1−/− glial cultures treated with 10 μM Aβ1-42 for 24–96 h analyzing ARG1, CCL22, YM1, CD206 and TGFβ anti-inflammatory glial marker expression levels. For Q-PCR all samples were normalized back to the Ct value of the housekeeping gene GAPDH (ΔCt). The mRNA of the Aβ1-42 treatment groups was then expressed relative to their gene-specific vehicle controls (fold change, ΔΔCt). Data are displayed as mean ± SEM (n = 4 (wildtype), n = 5 (IFNAR1−/−); *p < 0.05, **p < 0.01). See Additional file 2: Table S1 for further analysis
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Fig7: Aβ1-42 induces a pro-inflammatory phenotype in primary cultured glia with removal of IFNAR demonstrating a predmoninatly anti-inflammatory response. a Q-PCR of primary wildtype and IFNAR1−/− glial cultures treated with 10 μM Aβ1-42 for 24–96 h analyzing iNOS, CD11b and CD32 pro-inflammatory glial marker expression levels. b Q-PCR of primary wildtype and IFNAR1−/− glial cultures treated with 10 μM Aβ1-42 for 24–96 h analyzing ARG1, CCL22, YM1, CD206 and TGFβ anti-inflammatory glial marker expression levels. For Q-PCR all samples were normalized back to the Ct value of the housekeeping gene GAPDH (ΔCt). The mRNA of the Aβ1-42 treatment groups was then expressed relative to their gene-specific vehicle controls (fold change, ΔΔCt). Data are displayed as mean ± SEM (n = 4 (wildtype), n = 5 (IFNAR1−/−); *p < 0.05, **p < 0.01). See Additional file 2: Table S1 for further analysis
Mentions: Significantly, expression of the iNOS pro-inflammatory marker was elevated in wildtype but not IFNAR1−/− glial cultures in response to Aβ1-42 (24 h: Wildtype: 5.4 ± 2.8-fold vs. IFNAR1−/−: 1.1 ± 0.3-fold, p = 0.0195; 48 h: Wildtype: 5.9 ± 2.3-fold vs. IFNAR1−/−: 0.6 ± 0.06-fold, p = 0.0032, n = 4–5 per genotype, Fig. 7a). Transcript levels of the CD11b pro-inflammatory marker were also elevated in Aβ1-42-treated wildtype cultures but not when IFNAR1 was absent (72 h: Wildtype: 3.6 ± 0.9-fold vs. IFNAR1−/−: 0.7 ± 0.2-fold, p = 0.0274; 96 h: Wildtype: 4.1 ± 1.2-fold vs. IFNAR1−/−: 0.8 ± 0.2-fold, p = 0.0083, n = 4–5 per genotype, Fig. 7a). Expression levels of the CD32 pro-inflammatory marker were also reduced in IFNAR1−/− glial cultures when compared to wildtype counterparts upon Aβ1-42 insult (96 h: Wildtype: 4.6 ± 1.4-fold vs. IFNAR1−/−: 1.4 ± 0.2-fold, p = 0.0054, n = 4–5 per genotype, Fig. 7a).Fig. 7

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