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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

Astrocyte reactivity is elevated but microgliosis is dampened in APPSWE/PS1ΔE9 x IFNAR1−/− mice. a Representative cortical sections from 9 month old APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice stained with anti-GFAP using fluorescence immunohistochemistry. b Integrated density values of positive GFAP immunofluorescence were calculated from entire cortical regions of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice (3 sections per mouse). c High power magnification images of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mouse cortical sections triple-labelled with DAPI, anti-GFAP and anti-WO-2. d Representative cortical sections from 9 month old APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice stained with anti-IBA-1 using fluorescence immunohistochemistry. e Integrated density values of positive IBA-1 immunofluorescence were calculated from entire cortical regions of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice (3 sections per mouse). f High power magnification images of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mouse cortical sections triple-labelled with DAPI, anti-IBA-1 and anti-WO-2. b Scale bars: low power = 200 μm; high power = 30 μm. All data is displayed as box plots described in the statistical analysis section in Materials and Methods (n = 9 per genotype; •represents outlier value; **p < 0.01, ***p < 0.001). See Additional file 2: Table S1 for further analysis
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Fig4: Astrocyte reactivity is elevated but microgliosis is dampened in APPSWE/PS1ΔE9 x IFNAR1−/− mice. a Representative cortical sections from 9 month old APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice stained with anti-GFAP using fluorescence immunohistochemistry. b Integrated density values of positive GFAP immunofluorescence were calculated from entire cortical regions of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice (3 sections per mouse). c High power magnification images of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mouse cortical sections triple-labelled with DAPI, anti-GFAP and anti-WO-2. d Representative cortical sections from 9 month old APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice stained with anti-IBA-1 using fluorescence immunohistochemistry. e Integrated density values of positive IBA-1 immunofluorescence were calculated from entire cortical regions of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice (3 sections per mouse). f High power magnification images of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mouse cortical sections triple-labelled with DAPI, anti-IBA-1 and anti-WO-2. b Scale bars: low power = 200 μm; high power = 30 μm. All data is displayed as box plots described in the statistical analysis section in Materials and Methods (n = 9 per genotype; •represents outlier value; **p < 0.01, ***p < 0.001). See Additional file 2: Table S1 for further analysis

Mentions: Both microgliosis and astrocyte reactivity are important hallmarks of the neuro-inflammation evident in AD and are primary sources of pro-inflammatory cytokine production [25]. To establish if removal of type-1 IFN signaling alters astrocyte reactivity in APPSWE/PS1ΔE9 mice, immunohistochemistry was performed. Representative images and fluorescence quantification of sagittaly sectioned cortex revealed a significant 2.2 ± 0.3-fold increase in GFAP reactivity in APPSWE/PS1ΔE9 x IFNAR1−/− mice compared to APPSWE/PS1ΔE9 counterparts (p = 0.0006, n = 9 per genotype, Fig. 4a, b). High power magnification images demonstrate this elevated astrocyte reactivity surrounds Aβ plaques, generating a localized inflammatory environment (Fig. 4c). Collectively, this data highlights that removal of IFNAR1 triggers increased astrocyte reactivity in cortical areas of Aβ accumulation in APPSWE/PS1ΔE9 mice. However, further investigation is required to conclude if this is a compensatory or direct effect of removing type-1 IFN signaling in APPSWE/PS1ΔE9 mice.Fig. 4


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)

Astrocyte reactivity is elevated but microgliosis is dampened in APPSWE/PS1ΔE9 x IFNAR1−/− mice. a Representative cortical sections from 9 month old APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice stained with anti-GFAP using fluorescence immunohistochemistry. b Integrated density values of positive GFAP immunofluorescence were calculated from entire cortical regions of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice (3 sections per mouse). c High power magnification images of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mouse cortical sections triple-labelled with DAPI, anti-GFAP and anti-WO-2. d Representative cortical sections from 9 month old APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice stained with anti-IBA-1 using fluorescence immunohistochemistry. e Integrated density values of positive IBA-1 immunofluorescence were calculated from entire cortical regions of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice (3 sections per mouse). f High power magnification images of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mouse cortical sections triple-labelled with DAPI, anti-IBA-1 and anti-WO-2. b Scale bars: low power = 200 μm; high power = 30 μm. All data is displayed as box plots described in the statistical analysis section in Materials and Methods (n = 9 per genotype; •represents outlier value; **p < 0.01, ***p < 0.001). See Additional file 2: Table S1 for further analysis
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Related In: Results  -  Collection

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Fig4: Astrocyte reactivity is elevated but microgliosis is dampened in APPSWE/PS1ΔE9 x IFNAR1−/− mice. a Representative cortical sections from 9 month old APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice stained with anti-GFAP using fluorescence immunohistochemistry. b Integrated density values of positive GFAP immunofluorescence were calculated from entire cortical regions of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice (3 sections per mouse). c High power magnification images of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mouse cortical sections triple-labelled with DAPI, anti-GFAP and anti-WO-2. d Representative cortical sections from 9 month old APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice stained with anti-IBA-1 using fluorescence immunohistochemistry. e Integrated density values of positive IBA-1 immunofluorescence were calculated from entire cortical regions of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice (3 sections per mouse). f High power magnification images of APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mouse cortical sections triple-labelled with DAPI, anti-IBA-1 and anti-WO-2. b Scale bars: low power = 200 μm; high power = 30 μm. All data is displayed as box plots described in the statistical analysis section in Materials and Methods (n = 9 per genotype; •represents outlier value; **p < 0.01, ***p < 0.001). See Additional file 2: Table S1 for further analysis
Mentions: Both microgliosis and astrocyte reactivity are important hallmarks of the neuro-inflammation evident in AD and are primary sources of pro-inflammatory cytokine production [25]. To establish if removal of type-1 IFN signaling alters astrocyte reactivity in APPSWE/PS1ΔE9 mice, immunohistochemistry was performed. Representative images and fluorescence quantification of sagittaly sectioned cortex revealed a significant 2.2 ± 0.3-fold increase in GFAP reactivity in APPSWE/PS1ΔE9 x IFNAR1−/− mice compared to APPSWE/PS1ΔE9 counterparts (p = 0.0006, n = 9 per genotype, Fig. 4a, b). High power magnification images demonstrate this elevated astrocyte reactivity surrounds Aβ plaques, generating a localized inflammatory environment (Fig. 4c). Collectively, this data highlights that removal of IFNAR1 triggers increased astrocyte reactivity in cortical areas of Aβ accumulation in APPSWE/PS1ΔE9 mice. However, further investigation is required to conclude if this is a compensatory or direct effect of removing type-1 IFN signaling in APPSWE/PS1ΔE9 mice.Fig. 4

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