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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne, 3010, Victoria, Australia.
authors.forename: Myles R
authors.initials: MR
authors.lastname: Minter
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne, 3010, Victoria, Australia.
authors.forename: Zachery
authors.initials: Z
authors.lastname: Moore
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne, 3010, Victoria, Australia.
authors.forename: Moses
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne, 3010, Victoria, Australia.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Brody
authors.affiliation: Department of Medicine (The Royal Melbourne Hospital), Melbourne Brain Center, University of Melbourne, Parkville, Melbourne, Victoria, Australia.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
authors.affiliation: Department of Medicine (The Royal Melbourne Hospital), Melbourne Brain Center, University of Melbourne, Parkville, Melbourne, Victoria, Australia.
authors.forename: Sandy R
authors.initials: SR
authors.lastname: Shultz
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne, 3010, Victoria, Australia. juliett@unimelb.edu.au.
authors.forename: Juliet M
authors.initials: JM
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne, 3010, Victoria, Australia. pcrack@unimelb.edu.au.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crack
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000276:immunology / Q000473:pathology; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000276:immunology / Q000473:pathology / Q000523:psychology; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000276:immunology* / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000276:immunology / Q000473:pathology / Q000523:psychology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000235:genetics; D065852:Spatial Memory / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; C508032:Ifnar1 protein, mouse; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053633:Receptor, Interferon alpha-beta
keywords: Alzheimer’s disease; Amyloid-β; Cognition; Microglial polarization; Neuro-inflammation; Type-1 interferons