Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype

Myles R. Minter, Zachery Moore, Moses Zhang, Kate M. Brody, Nigel C. Jones, Sandy R. Shultz, Juliet M. Taylor, Peter J. Crack

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Number of pages23
JournalActa neuropathologica communications
Volume4
Issue number1
DOIs
Publication statusPublished - 11 Jul 2016
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • Amyloid-β
  • Cognition
  • Microglial polarization
  • Neuro-inflammation
  • Type-1 interferons

Cite this

Minter, Myles R. ; Moore, Zachery ; Zhang, Moses ; Brody, Kate M. ; Jones, Nigel C. ; Shultz, Sandy R. ; Taylor, Juliet M. ; Crack, Peter J. / Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype. In: Acta neuropathologica communications. 2016 ; Vol. 4, No. 1.
@article{3c36b8a960cc4cb0a6735697160cd55d,
title = "Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype",
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.",
keywords = "Alzheimer’s disease, Amyloid-β, Cognition, Microglial polarization, Neuro-inflammation, Type-1 interferons",
author = "Minter, {Myles R.} and Zachery Moore and Moses Zhang and Brody, {Kate M.} and Jones, {Nigel C.} and Shultz, {Sandy R.} and Taylor, {Juliet M.} and Crack, {Peter J.}",
year = "2016",
month = "7",
day = "11",
doi = "10.1186/s40478-016-0341-4",
language = "English",
volume = "4",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "Springer-Verlag London Ltd.",
number = "1",

}

Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype. / Minter, Myles R.; Moore, Zachery; Zhang, Moses; Brody, Kate M.; Jones, Nigel C.; Shultz, Sandy R.; Taylor, Juliet M.; Crack, Peter J.

In: Acta neuropathologica communications, Vol. 4, No. 1, 11.07.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype

AU - Minter, Myles R.

AU - Moore, Zachery

AU - Zhang, Moses

AU - Brody, Kate M.

AU - Jones, Nigel C.

AU - Shultz, Sandy R.

AU - Taylor, Juliet M.

AU - Crack, Peter J.

PY - 2016/7/11

Y1 - 2016/7/11

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Amyloid-β

KW - Cognition

KW - Microglial polarization

KW - Neuro-inflammation

KW - Type-1 interferons

UR - http://www.scopus.com/inward/record.url?scp=85015834418&partnerID=8YFLogxK

U2 - 10.1186/s40478-016-0341-4

DO - 10.1186/s40478-016-0341-4

M3 - Article

VL - 4

JO - Acta neuropathologica communications

JF - Acta neuropathologica communications

SN - 2051-5960

IS - 1

ER -