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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

APPSWE/PS1ΔE9 x IFNAR1−/− mice are spared from cognitive impairment. Wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls 9 months of age were subjected to Morris water maze testing to assess spatial learning and memory. All mice were tested using a 7-day hidden platform acquisition (4trials/day) with probe trial protocol as described in Materials and Methods. Primary water maze readouts of a average trial latency, b trial success rate and c trial path length (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, WT vs. APPSWE/PS1ΔE9; θp < 0.05, θθp < 0.01, θθθp < 0.001, θθθθp < 0.0001, WT vs. APPSWE/PS1ΔE9 x IFNAR1−/−; +p < 0.05, ++p < 0.01, +++p < 0.001 WT vs. IFNAR1−/−). d Representative automated tracks from day 7 testing is shown for all genotypes. e After day 7 acquisition the escape platform is removed from the maze and mice are introduced into the maze for a final trial. Quantification of the time spent in the platform containing quadrant for all genotypes is shown. The dashed line (y = 25 %) represents the percentage of time spent in the escape quadrant that would be solely due to random chance as opposed to preference (p < 0.05). f Calculation of average swim velocity across all 7 days of testing is shown for all genotypes (**p < 0.01). Data is displayed as mean ± SEM or box plots described in the statistical analysis section in Materials and Methods (n = 14 (APPSWE/PS1ΔE9), n = 9 (APPSWE/PS1ΔE9 x IFNAR1−/−), n = 18 (IFNAR1−/−), n = 15 (wildtype)). See Additional file 2: Table S1 for further analysis
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Fig2: APPSWE/PS1ΔE9 x IFNAR1−/− mice are spared from cognitive impairment. Wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls 9 months of age were subjected to Morris water maze testing to assess spatial learning and memory. All mice were tested using a 7-day hidden platform acquisition (4trials/day) with probe trial protocol as described in Materials and Methods. Primary water maze readouts of a average trial latency, b trial success rate and c trial path length (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, WT vs. APPSWE/PS1ΔE9; θp < 0.05, θθp < 0.01, θθθp < 0.001, θθθθp < 0.0001, WT vs. APPSWE/PS1ΔE9 x IFNAR1−/−; +p < 0.05, ++p < 0.01, +++p < 0.001 WT vs. IFNAR1−/−). d Representative automated tracks from day 7 testing is shown for all genotypes. e After day 7 acquisition the escape platform is removed from the maze and mice are introduced into the maze for a final trial. Quantification of the time spent in the platform containing quadrant for all genotypes is shown. The dashed line (y = 25 %) represents the percentage of time spent in the escape quadrant that would be solely due to random chance as opposed to preference (p < 0.05). f Calculation of average swim velocity across all 7 days of testing is shown for all genotypes (**p < 0.01). Data is displayed as mean ± SEM or box plots described in the statistical analysis section in Materials and Methods (n = 14 (APPSWE/PS1ΔE9), n = 9 (APPSWE/PS1ΔE9 x IFNAR1−/−), n = 18 (IFNAR1−/−), n = 15 (wildtype)). See Additional file 2: Table S1 for further analysis

Mentions: To assess if removal of type-1 IFN signaling can alleviate the cognitive deficits observed in APPSWE/PS1ΔE9 we analyzed spatial learning and memory performance of wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice using the Morris water maze. Compared to wildtype, APPSWE/PS1ΔE9 mice required more time to find the escape platform, whilst APPSWE/PS1ΔE9 x IFNAR1−/− mice were initially impaired but recovered to wildtype levels as pheno-copied by IFNAR1−/− mice (n = 9–18 per genotype, 0.05 < p < 0.001, Fig. 2a). Compared to wildtype, an initial decline in trial success rate was seen for all genotypes but this was only maintained by the APPSWE/PS1ΔE9 mice over the course of acquisition (n = 9–18 per genotype, 0.05 < p < 0.0001, Fig. 2b). Compared to wildtype, all genotypes initially selected longer escape paths but only APPSWE/PS1ΔE9 mice maintained this abnormality throughout testing (n = 9–18 per genotype, p < 0.01, Fig. 2c). Representative tracks (Day 7 acquisition) of APPSWE/PS1ΔE9 mice display a lack of cue-directed swimming to find the platform, partially rectified in the APPSWE/PS1ΔE9 IFNAR1−/− counterparts. Wildtype and IFNAR1−/− behaved similarly (Fig. 2d, Additional file 2: Table S1 for detailed analysis).Fig. 2


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)

APPSWE/PS1ΔE9 x IFNAR1−/− mice are spared from cognitive impairment. Wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls 9 months of age were subjected to Morris water maze testing to assess spatial learning and memory. All mice were tested using a 7-day hidden platform acquisition (4trials/day) with probe trial protocol as described in Materials and Methods. Primary water maze readouts of a average trial latency, b trial success rate and c trial path length (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, WT vs. APPSWE/PS1ΔE9; θp < 0.05, θθp < 0.01, θθθp < 0.001, θθθθp < 0.0001, WT vs. APPSWE/PS1ΔE9 x IFNAR1−/−; +p < 0.05, ++p < 0.01, +++p < 0.001 WT vs. IFNAR1−/−). d Representative automated tracks from day 7 testing is shown for all genotypes. e After day 7 acquisition the escape platform is removed from the maze and mice are introduced into the maze for a final trial. Quantification of the time spent in the platform containing quadrant for all genotypes is shown. The dashed line (y = 25 %) represents the percentage of time spent in the escape quadrant that would be solely due to random chance as opposed to preference (p < 0.05). f Calculation of average swim velocity across all 7 days of testing is shown for all genotypes (**p < 0.01). Data is displayed as mean ± SEM or box plots described in the statistical analysis section in Materials and Methods (n = 14 (APPSWE/PS1ΔE9), n = 9 (APPSWE/PS1ΔE9 x IFNAR1−/−), n = 18 (IFNAR1−/−), n = 15 (wildtype)). See Additional file 2: Table S1 for further analysis
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Related In: Results  -  Collection

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Fig2: APPSWE/PS1ΔE9 x IFNAR1−/− mice are spared from cognitive impairment. Wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− littermate controls 9 months of age were subjected to Morris water maze testing to assess spatial learning and memory. All mice were tested using a 7-day hidden platform acquisition (4trials/day) with probe trial protocol as described in Materials and Methods. Primary water maze readouts of a average trial latency, b trial success rate and c trial path length (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, WT vs. APPSWE/PS1ΔE9; θp < 0.05, θθp < 0.01, θθθp < 0.001, θθθθp < 0.0001, WT vs. APPSWE/PS1ΔE9 x IFNAR1−/−; +p < 0.05, ++p < 0.01, +++p < 0.001 WT vs. IFNAR1−/−). d Representative automated tracks from day 7 testing is shown for all genotypes. e After day 7 acquisition the escape platform is removed from the maze and mice are introduced into the maze for a final trial. Quantification of the time spent in the platform containing quadrant for all genotypes is shown. The dashed line (y = 25 %) represents the percentage of time spent in the escape quadrant that would be solely due to random chance as opposed to preference (p < 0.05). f Calculation of average swim velocity across all 7 days of testing is shown for all genotypes (**p < 0.01). Data is displayed as mean ± SEM or box plots described in the statistical analysis section in Materials and Methods (n = 14 (APPSWE/PS1ΔE9), n = 9 (APPSWE/PS1ΔE9 x IFNAR1−/−), n = 18 (IFNAR1−/−), n = 15 (wildtype)). See Additional file 2: Table S1 for further analysis
Mentions: To assess if removal of type-1 IFN signaling can alleviate the cognitive deficits observed in APPSWE/PS1ΔE9 we analyzed spatial learning and memory performance of wildtype, IFNAR1−/−, APPSWE/PS1ΔE9 and APPSWE/PS1ΔE9 x IFNAR1−/− mice using the Morris water maze. Compared to wildtype, APPSWE/PS1ΔE9 mice required more time to find the escape platform, whilst APPSWE/PS1ΔE9 x IFNAR1−/− mice were initially impaired but recovered to wildtype levels as pheno-copied by IFNAR1−/− mice (n = 9–18 per genotype, 0.05 < p < 0.001, Fig. 2a). Compared to wildtype, an initial decline in trial success rate was seen for all genotypes but this was only maintained by the APPSWE/PS1ΔE9 mice over the course of acquisition (n = 9–18 per genotype, 0.05 < p < 0.0001, Fig. 2b). Compared to wildtype, all genotypes initially selected longer escape paths but only APPSWE/PS1ΔE9 mice maintained this abnormality throughout testing (n = 9–18 per genotype, p < 0.01, Fig. 2c). Representative tracks (Day 7 acquisition) of APPSWE/PS1ΔE9 mice display a lack of cue-directed swimming to find the platform, partially rectified in the APPSWE/PS1ΔE9 IFNAR1−/− counterparts. Wildtype and IFNAR1−/− behaved similarly (Fig. 2d, Additional file 2: Table S1 for detailed analysis).Fig. 2

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