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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-conditioned media from IFNAR1−/− glia induces less neurotoxicity than wildtype counterparts. Primary wildtype and IFNAR1−/− glial cultures were treated with 10 μM Aβ1-42 for 24–48 h and conditioned media was transferred to primary cultured wildtype neurons. An MTS assay was performed to assess cellular viability of neuronal cultures. Apoptosis-inducing staurosporine treatment was utilized as a cytotoxic positive control. Data are displayed as mean ± SEM (n = 3 per genotype (independent glial and neuronal primary cultures); ***p < 0.001). See Additional file 2: Table S1 for further analysis
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Fig8: Aβ1-42-conditioned media from IFNAR1−/− glia induces less neurotoxicity than wildtype counterparts. Primary wildtype and IFNAR1−/− glial cultures were treated with 10 μM Aβ1-42 for 24–48 h and conditioned media was transferred to primary cultured wildtype neurons. An MTS assay was performed to assess cellular viability of neuronal cultures. Apoptosis-inducing staurosporine treatment was utilized as a cytotoxic positive control. Data are displayed as mean ± SEM (n = 3 per genotype (independent glial and neuronal primary cultures); ***p < 0.001). See Additional file 2: Table S1 for further analysis

Mentions: To investigate the contribution of the glial polarized inflammatory response to Aβ1-42 on neuronal viability, primary wildtype and IFNAR1−/− mixed glial cultures were treated with 10 μM Aβ1-42 for 24–48 h and media was collected. Primary wildtype neuronal cultures were then supplemented with this media for 48 h and an MTS assay was performed to assess cellular viability. Significantly, treatment of neurons with wildtype glial conditioned media induced severe cytotoxicity that was attenuated when the same neurons were supplemented with IFNAR1−/− glial conditioned media (24 h media: Wildtype: 28.9 ± 1.2 % vs. IFNAR1−/−: 77.8 ± 5.7 %, p = 0.0003; 48 h media: Wildtype: 18.4 ± 1.9 % vs. IFNAR1−/−: 85.1 ± 7.1 %, p = 0.0001, n = 3 individual neuronal and glial cultures per genotype, Fig. 8). Both genotypes showed equal susceptibility to staurosporine-induced apoptosis. This data implies that the reduced Aβ1-42-induced pro-inflammatory cytokine burden and anti-inflammatory activity identified in IFNAR1−/− glia is protective to neurons in vitro.Fig. 8


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-conditioned media from IFNAR1−/− glia induces less neurotoxicity than wildtype counterparts. Primary wildtype and IFNAR1−/− glial cultures were treated with 10 μM Aβ1-42 for 24–48 h and conditioned media was transferred to primary cultured wildtype neurons. An MTS assay was performed to assess cellular viability of neuronal cultures. Apoptosis-inducing staurosporine treatment was utilized as a cytotoxic positive control. Data are displayed as mean ± SEM (n = 3 per genotype (independent glial and neuronal primary cultures); ***p < 0.001). See Additional file 2: Table S1 for further analysis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940712&req=5

Fig8: Aβ1-42-conditioned media from IFNAR1−/− glia induces less neurotoxicity than wildtype counterparts. Primary wildtype and IFNAR1−/− glial cultures were treated with 10 μM Aβ1-42 for 24–48 h and conditioned media was transferred to primary cultured wildtype neurons. An MTS assay was performed to assess cellular viability of neuronal cultures. Apoptosis-inducing staurosporine treatment was utilized as a cytotoxic positive control. Data are displayed as mean ± SEM (n = 3 per genotype (independent glial and neuronal primary cultures); ***p < 0.001). See Additional file 2: Table S1 for further analysis
Mentions: To investigate the contribution of the glial polarized inflammatory response to Aβ1-42 on neuronal viability, primary wildtype and IFNAR1−/− mixed glial cultures were treated with 10 μM Aβ1-42 for 24–48 h and media was collected. Primary wildtype neuronal cultures were then supplemented with this media for 48 h and an MTS assay was performed to assess cellular viability. Significantly, treatment of neurons with wildtype glial conditioned media induced severe cytotoxicity that was attenuated when the same neurons were supplemented with IFNAR1−/− glial conditioned media (24 h media: Wildtype: 28.9 ± 1.2 % vs. IFNAR1−/−: 77.8 ± 5.7 %, p = 0.0003; 48 h media: Wildtype: 18.4 ± 1.9 % vs. IFNAR1−/−: 85.1 ± 7.1 %, p = 0.0001, n = 3 individual neuronal and glial cultures per genotype, Fig. 8). Both genotypes showed equal susceptibility to staurosporine-induced apoptosis. This data implies that the reduced Aβ1-42-induced pro-inflammatory cytokine burden and anti-inflammatory activity identified in IFNAR1−/− glia is protective to neurons in vitro.Fig. 8

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