Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 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(Delta E9) mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APP(SWE)/PS1(Delta E9) 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(Delta E9) x IFNAR1(-/-) mice displayed a modest reduction in A beta 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(Delta E9) mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1(Delta E9) x IFNAR1(-/-) mice compared to APP(SWE)/PS1(Delta E9) mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APP(SWE)/PS1(Delta E9) x IFNAR1(-/-) mice in comparison to APP(SWE)/PS1(Delta E9) mice. These APP(SWE)/PS1(Delta E9) x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble A beta 1-42 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.