Deletion of the type-1 interferon receptor in APP(SWE)/PS1(ΔE9) mice preserves cognitive function and alters glial phenotype

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 APP(SWE)/PS1(ΔE9) mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APP(SWE)/PS1(ΔE9) x IFNAR1(−/−)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APP(SWE)/PS1(ΔE9) 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 APP(SWE)/PS1(ΔE9) mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APP(SWE)/PS1(ΔE9) x IFNAR1(−/−) mice compared to APP(SWE)/PS1(ΔE9) mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APP(SWE)/PS1(ΔE9) x IFNAR1(−/−) mice in comparison to APP(SWE)/PS1(ΔE9) mice. These APP(SWE)/PS1(ΔE9) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-016-0341-4) contains supplementary material, which is available to authorized users.