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Cited by 79Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

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

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Minter, Myles R., Moore, Zachery, Zhang, Moses, Brody, Kate M., Jones, Nigel C., Shultz, Sandy R., Taylor, Juliet M., Crack, Peter J.·2016·Acta Neuropathologica Communications
DOI 10.1186/s40478-016-0341-4PMC PMC4940712
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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.

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  • In APP/PS1 mice and 5xFAD mice, loss of type I IFN signaling is protective, ameliorating Aβ pathology and attenuating neurotoxicity, synapse loss, and microglial activation.

    “In APP/PS1 mice and 5xFAD mice, loss of type I IFN signaling is protective ameliorating the Aβ pathology and attenuating neurotoxicity, synapse loss, and microglial activation.”

    From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [93]

    The Introduction and Discussion report that IFNAR1 deletion in APP/PS1 mice improved spatial cognition and reduced microgliosis; the Discussion also describes a neuroprotective effect in cultured cells. But the paper studies APP/PS1 mice, not 5xFAD mice, and does not establish reduced synapse loss. It reports only a modest reduction in soluble Aβ, with plaque deposition unchanged, so the broad claim of ameliorated Aβ pathology overstates its findings. Page numbers were not provided in our copy. (LLM, conf=0.90)

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Authors
Minter, M. R., Moore, Z., Zhang, M., Brody, K. M., Jones, N. C., Shultz, S. R., Taylor, J. M., & Crack, P. J.
Affiliations
  • The University of Melbourne (AU)
  • The Royal Melbourne Hospital (AU)
Corresponding author
  • Taylor, Juliet M.
  • Crack, Peter J.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2016-07-11
Volume
4
Issue
1
Pages
72-72
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-016-0341-4
PMC
PMC4940712
OpenAlex
W2474970585
Cited by
79
References
9
Citations by year
2026: 7 · 2025: 10 · 2024: 6 · 2023: 12 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 3 · 2017: 12 · 2016: 1
FWCI
6.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • National Health and Medical Research Council (NHMRC) of Australia (1044714)
  • NHMRC (1044714)
  • Australian Research Counci (Future Fellowship)
  • Alzheimer’s Australia Dementia Research Fund
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
type I interferon signaling, IFNAR1, Alzheimer's disease, APPswe/PS1ΔE9 mice, neuroinflammation, amyloid-beta, amyloid plaques, spatial learning and memory, astrocyte activation, microglial activation, inflammatory cytokines, innate immunity
MeSH terms
Alzheimer Disease, Animals, Cells, Cultured, Cerebral Cortex, Cognition, Disease Models, Animal, Female, Gliosis, Hippocampus, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neuroglia, Neurons, Peptide Fragments, Amyloid beta-Peptides, Maze Learning, Mice, Receptor, Interferon alpha-beta, Plaque, Amyloid, Spatial Memory

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