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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0341-4) contains supplementary material, which is available to authorized users.

Type I interferon pathway in CNS homeostasis and neurological disorders

“…Interestingly, HSV-1 uses a specialized CNS entry pathway-it enters the nerve terminal in peripheral organs, then uses neural transport mechanisms to transport the virions to the neuron cell body where replication occurs (Conrady, Drevets, & Carr, 2010). When the type I interferon receptor (IFNAR) is deleted in APP SWE /PS1 DE9 mice, which result in an Alzheimer s mouse model, a modest reduction in cortical amyloid-beta peptide load is detected in conjunction with improved spatial learning and memory capacities (Minter et al, 2016). Notably, these genetic defects often appear to display incomplete penetrance, however they all share the common feature of reduced type I IFN responses after HSV-1 infection (Zhang et al, 2013b).…”

“…downregulating pro-inflammatory factors [such as inducible nitric oxide synthases (iNOS), integrin aM (CD11b), and Siglec-3 (CD33)] and the upregulation of anti-inflammatory phenotypic markers (transforming growth factor beta (TGF-ß), chitinase-like protein 3 (YM1), arginase 1 (ARG1), and triggering receptor expressed on myeloid cells 2 (TREM2))(Minter et al, 2016). It was concluded from initial studies that IFN-b exerts a direct effect on neurons, providing a certain degree of protection against neurotoxic and inflammatory insults(Di Filippo et al, 2014).…”

Exosomal biomarkers in Down syndrome and Alzheimer's disease

“…In fact, several lines of evidence indicate that IFN signaling could accelerate the progression of AD. In animal models and human cell-based models, IFN signaling was shown to enhance APP expression and processing into the pathological amyloid peptide, Aβ 1-42 , leading to increased amyloid plaque formation (Hong et al 2003; Minter et al 2016). In mouse models of AD, IFN signaling mediates neuroinflammation, neuronal cell death, and cognitive decline downstream of amyloid plaque formation (Browne et al 2013; Yamamoto et al 2007; Minter et al 2016; Taylor et al 2014).…”

“…In animal models and human cell-based models, IFN signaling was shown to enhance APP expression and processing into the pathological amyloid peptide, Aβ 1-42 , leading to increased amyloid plaque formation (Hong et al 2003; Minter et al 2016). In mouse models of AD, IFN signaling mediates neuroinflammation, neuronal cell death, and cognitive decline downstream of amyloid plaque formation (Browne et al 2013; Yamamoto et al 2007; Minter et al 2016; Taylor et al 2014). In fact, knockout of either of the T21-related IFNAR1 or IFNGR2 receptors was sufficient to prevent disease progression in these models (Yamamoto et al 2007; Minter et al 2016).…”

“…In mouse models of AD, IFN signaling mediates neuroinflammation, neuronal cell death, and cognitive decline downstream of amyloid plaque formation (Browne et al 2013; Yamamoto et al 2007; Minter et al 2016; Taylor et al 2014). In fact, knockout of either of the T21-related IFNAR1 or IFNGR2 receptors was sufficient to prevent disease progression in these models (Yamamoto et al 2007; Minter et al 2016). Furthermore, in a longitudinal study of inflammatory proteins in plasma, increased circulating levels of IFN-gamma as well as key IFN-inducible cytokines, such as IL6 (Zimmermann et al 2016; Jordan et al 2007; Duddy et al 1999), were found to correlate with faster AD progression (Leung et al 2013).…”