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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

Schematic of the modulated neuro-inflammatory environment in APPSWE/PS1ΔE9 x IFNAR1−/− mice. The current study provides evidence that a type-1 IFN response contributes to the neuro-inflammation observed in AD. Amyloid plaques and soluble Aβ1-42 within the plaque microenvironment triggers pro-inflammatory microglial activation and secretion of pro-inflammatory cytokines, initiating the neuro-inflammatory process. The pro-inflammatory cues within the plaque microenvironment further enhance gliosis, exacerbating inflammation. In AD, excessive Aβ production maintains the stimulus for a pro-inflammatory response, compromising resolution, and contributes to a self-perpetuating neuro-degenerative inflammatory cycle. The current study demonstrates that type-1 IFN signaling intricately controls this neuro-inflammation. Removal of IFNAR1 in APPSWE/PS1ΔE9 mice reduced type-1 IFN production, TNFα expression and conferred an anti-inflammatory and neuro-protective anti-inflammatory activation state of microglia. Enhanced astrocyte reactivity and IL-1β expression, but decreased total microgliosis, was also demonstrated in these mice which were protected from spatial learning and memory deficits at 9 months of age
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Fig9: Schematic of the modulated neuro-inflammatory environment in APPSWE/PS1ΔE9 x IFNAR1−/− mice. The current study provides evidence that a type-1 IFN response contributes to the neuro-inflammation observed in AD. Amyloid plaques and soluble Aβ1-42 within the plaque microenvironment triggers pro-inflammatory microglial activation and secretion of pro-inflammatory cytokines, initiating the neuro-inflammatory process. The pro-inflammatory cues within the plaque microenvironment further enhance gliosis, exacerbating inflammation. In AD, excessive Aβ production maintains the stimulus for a pro-inflammatory response, compromising resolution, and contributes to a self-perpetuating neuro-degenerative inflammatory cycle. The current study demonstrates that type-1 IFN signaling intricately controls this neuro-inflammation. Removal of IFNAR1 in APPSWE/PS1ΔE9 mice reduced type-1 IFN production, TNFα expression and conferred an anti-inflammatory and neuro-protective anti-inflammatory activation state of microglia. Enhanced astrocyte reactivity and IL-1β expression, but decreased total microgliosis, was also demonstrated in these mice which were protected from spatial learning and memory deficits at 9 months of age

Mentions: The precise mechanism of how Aβ drives neurotoxicity and exacerbation of AD remains largely unknown. Neuro-inflammation has been routinely implicated in AD and is gaining credence as a major facilitator of disease progression [25, 41, 46, 47]. Type-1 IFNs are master regulators of the innate immune response [33] regulating IL-1β, IL-6 and TNFα cytokine secretion that remain up-regulated in AD [42, 43]. The present study was designed to test the hypothesis that type-1 IFN signalling influences neuro-inflammation and subsequent pathology in the APPSWE/PS1ΔE9 mouse model of AD. To address this hypothesis we generated APPSWE/PS1ΔE9 x IFNAR1−/− mice lacking type-1 IFN signaling. We identified that these mice were protected from spatial learning and memory deficits demonstrated by APPSWE/PS1ΔE9 mice. Interestingly, this phenotypic rescue did not correlate with alterations in Aβ plaque burden and only modest reductions in soluble cortical Aβ monomers were detected. Additionally, removal IFNAR1 in the APPSWE/PS1ΔE9 mouse promoted cortical astrocyte reactivity, decreased total microgliosis, and conferred a largely anti-inflammatory glial phenotype. These findings were corroborated with IFNAR1−/− glial cultures initiating a predominantly anti-inflammatory response to in vitro Aβ1-42 insult (Fig. 9).Fig. 9


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)

Schematic of the modulated neuro-inflammatory environment in APPSWE/PS1ΔE9 x IFNAR1−/− mice. The current study provides evidence that a type-1 IFN response contributes to the neuro-inflammation observed in AD. Amyloid plaques and soluble Aβ1-42 within the plaque microenvironment triggers pro-inflammatory microglial activation and secretion of pro-inflammatory cytokines, initiating the neuro-inflammatory process. The pro-inflammatory cues within the plaque microenvironment further enhance gliosis, exacerbating inflammation. In AD, excessive Aβ production maintains the stimulus for a pro-inflammatory response, compromising resolution, and contributes to a self-perpetuating neuro-degenerative inflammatory cycle. The current study demonstrates that type-1 IFN signaling intricately controls this neuro-inflammation. Removal of IFNAR1 in APPSWE/PS1ΔE9 mice reduced type-1 IFN production, TNFα expression and conferred an anti-inflammatory and neuro-protective anti-inflammatory activation state of microglia. Enhanced astrocyte reactivity and IL-1β expression, but decreased total microgliosis, was also demonstrated in these mice which were protected from spatial learning and memory deficits at 9 months of age
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig9: Schematic of the modulated neuro-inflammatory environment in APPSWE/PS1ΔE9 x IFNAR1−/− mice. The current study provides evidence that a type-1 IFN response contributes to the neuro-inflammation observed in AD. Amyloid plaques and soluble Aβ1-42 within the plaque microenvironment triggers pro-inflammatory microglial activation and secretion of pro-inflammatory cytokines, initiating the neuro-inflammatory process. The pro-inflammatory cues within the plaque microenvironment further enhance gliosis, exacerbating inflammation. In AD, excessive Aβ production maintains the stimulus for a pro-inflammatory response, compromising resolution, and contributes to a self-perpetuating neuro-degenerative inflammatory cycle. The current study demonstrates that type-1 IFN signaling intricately controls this neuro-inflammation. Removal of IFNAR1 in APPSWE/PS1ΔE9 mice reduced type-1 IFN production, TNFα expression and conferred an anti-inflammatory and neuro-protective anti-inflammatory activation state of microglia. Enhanced astrocyte reactivity and IL-1β expression, but decreased total microgliosis, was also demonstrated in these mice which were protected from spatial learning and memory deficits at 9 months of age
Mentions: The precise mechanism of how Aβ drives neurotoxicity and exacerbation of AD remains largely unknown. Neuro-inflammation has been routinely implicated in AD and is gaining credence as a major facilitator of disease progression [25, 41, 46, 47]. Type-1 IFNs are master regulators of the innate immune response [33] regulating IL-1β, IL-6 and TNFα cytokine secretion that remain up-regulated in AD [42, 43]. The present study was designed to test the hypothesis that type-1 IFN signalling influences neuro-inflammation and subsequent pathology in the APPSWE/PS1ΔE9 mouse model of AD. To address this hypothesis we generated APPSWE/PS1ΔE9 x IFNAR1−/− mice lacking type-1 IFN signaling. We identified that these mice were protected from spatial learning and memory deficits demonstrated by APPSWE/PS1ΔE9 mice. Interestingly, this phenotypic rescue did not correlate with alterations in Aβ plaque burden and only modest reductions in soluble cortical Aβ monomers were detected. Additionally, removal IFNAR1 in the APPSWE/PS1ΔE9 mouse promoted cortical astrocyte reactivity, decreased total microgliosis, and conferred a largely anti-inflammatory glial phenotype. These findings were corroborated with IFNAR1−/− glial cultures initiating a predominantly anti-inflammatory response to in vitro Aβ1-42 insult (Fig. 9).Fig. 9

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