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.

Past research in Alzheimer's disease (AD) has largely been driven by the amyloid hypothesis; the accompanying neuroinflammation seen in AD has been assumed to be consequential and not disease modifying or causative. However, recent data from both clinical and preclinical studies have established that the immune-driven neuroinflammation contributes to AD pathology. Key evidence for the involvement of neuroinflammation in AD includes enhanced microglial and astroglial activation in the brains of AD patients, increased pro-inflammatory cytokine burden in AD brains, and epidemiological evidence that chronic non-steroidal anti-inflammatory drug use prior to disease onset leads to a lower incidence of AD. Identifying critical mediators controlling this neuroinflammation will prove beneficial in developing anti-inflammatory therapies for the treatment of AD. The type-I interferons (IFNs) are pleiotropic cytokines that control pro-inflammatory cytokine secretion and are master regulators of the innate immune response that impact on disorders of the central nervous system. This review provides evidence that the type-I IFNs play a critical role in the exacerbation of neuroinflammation and actively contribute to the progression of AD.

Neuroinflammation and accompanying microglial dysfunction are now appreciated to be involved in Alzheimer's disease (AD) pathogenesis. Critical to the process of neuroinflammation are the type-I interferon (IFN) family of cytokines. Efforts to phenotypically characterize microglia within AD identify distinct populations associated with type-I IFN signalling, yet how this affects underlying microglial function is yet to be fully elucidated. Here we demonstrate that Aβ 1-42 exposure increases bioactive levels of type-I IFN produced by primary microglia alongside increased expression of type-I IFN related genes. primary microglia isolated from brains of App swe PS1 ΔE9 mice with ablated type-I IFN signalling show an increased phagocytic ability to uptake FITC-Aβ 1-42 . Correlative assessment of plaque sizes in aged App swe PS1 ΔE9 mice with abrogated type-I IFN signalling show unchanged deposition levels. Microglia from these mice did however show alterations in morphology. This data further highlights the role of type-I IFN signalling within microglia and identifies a role in phagocytosis. As such, targeting both microglial and global type-I IFN signalling presents as a novel therapeutic strategy for AD management.Alzheimer's disease (AD) is now recognised as the most common form of dementia and is now estimated to be the 5 th largest cause of death globally 1 . AD has been classically characterised by its two hallmark pathologies, neurofibrillary tangles composed of hyper phosphorylated tau, and extracellular senile plaques composed of amyloid beta (Aβ). The immune response to these pathologies, neuroinflammation is now appreciated to be involved in disease progression. Regulated forms of neuroinflammation are viewed as protective, and indeed required for homeostatic function. In contrast, a dysregulated form of this process is present in AD 2 . This dysregulated form is now recognised as a contributor to AD pathogenesis.Fundamental to this neuroinflammation are microglia, the resident innate immune cells within the central nervous system (CNS). Critically, microglia mount the initial neuroinflammatory response and further maintain it 3 . Upon recognition of noxious stimuli, microglia release a number of cytokines including interleukin (IL) 1β, IL6, and tumor necrosis factor alpha (TNFα) to create an inflammatory microenvironment 4 . This is seen in conjunction with chemokine secretion to recruit additional microglia. Microglia also have a number of roles outside immune-related functions. In particular, microglia are often viewed as macrophages of the CNS due to a shared hierarchal lineage and roles in phagocytosis 5 .Due to diverse roles, microglia adopt a number of varied phenotypes with differential corresponding functions throughout the CNS. As such, large efforts have been made to better phenotypically characterize microglia under both normal and AD settings, primarily through transcriptomic-based approaches 6,7 . In the 5× familial AD mouse model, a single cell ribonucleic acid (RNA) -seq approach was used t...

Autism Spectrum Disorder (ASD; autism) is a neurodevelopmental disorder characterised by deficits in social communication, and restricted and/or repetitive behaviours. While the precise pathophysiologies are unclear, increasing evidence supports a role for dysregulated neuroinflammation in the brain with potential effects on synapse function. Here, we studied characteristics of microglia and astrocytes in the Neuroligin-3 (NL3 R451C) mouse model of autism since these cell types are involved in regulating both immune and synapse function. We observed increased microglial density in the dentate gyrus (DG) of NL3 R451C mice without morphological differences. In contrast, WT and NL3 R451C mice had similar astrocyte density but astrocyte branch length, the number of branch points, as well as cell radius and area were reduced in the DG of NL3 R451C mice. Because retraction of astrocytic processes has been linked to altered synaptic transmission and dendrite formation, we assessed for regional changes in pre-and postsynaptic protein expression in the cortex, striatum and cerebellum in NL3 R451C mice. NL3 R451C mice showed increased striatal postsynaptic density 95 (PSD-95) protein levels and decreased cortical expression of synaptosomal-associated protein 25 (SNAP-25). These changes could contribute to dysregulated neurotransmission and cognition deficits previously reported in these mice. Autism Spectrum Disorder (ASD; autism) is a neurodevelopmental disorder estimated to affect 1 in 54 children 1. Autism is characterised by deficits in social communication, and restricted and/or repetitive patterns of behaviour 2. A complex interaction between genetic and environmental factors is thought to contribute to autism. The clinical heterogeneity and variability in presentation and severity of autism has made diagnosis, treatment and the study of autism-relevant neurobiology challenging 3. However, functional and neuroanatomical abnormalities are consistently reported in autism patients 4-6 , with increasing evidence supporting a role for neuroinflammation in autism pathophysiology 7-9. Neuroinflammation involves the sustained, and often unwarranted, increase in activity of glial cells (i.e. microglia and astrocytes), which release many pro-inflammatory cytokines and chemokines in response to injury, infection or disease. During this activity, 'reactive' microglia and astrocytes show altered morphology. Aberrant neuroimmune profiles have been documented in autism including increased densities of reactive microglia and astrocytes in several brain regions 10-12 accompanied by alterations in cytokine and chemokine secretion in brain tissue 10,13 , cerebrospinal fluid 10,14 and blood 15-17 of autism patients compared to neurotypical controls. In addition to regulating immune function, microglia and astrocytes assist in maintaining synaptic function. Abnormal glial function may therefore influence synaptic circuitry and neuronal connectivity within the central nervous system (CNS) and contribute to regional-specific under-connecti...

First described clinically in 1906, Alzheimer's disease (AD) is the most common neurodegenerative disease and form of dementia worldwide. Despite its prevalence, only five therapies are currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. A multitude of experimental evidence has suggested that the once thought inconsequential process of neuroinflammation does, in fact, contribute to the AD pathogenesis. One such CNS cell type critical to this process are microglia. Plastic in nature with varied roles, microglia are emerging as key contributors to AD pathology. This review will focus on the role of microglia in the neuroinflammatory response in AD, highlighting recent studies implicating aberrant changes in microglial function in disease progression. Of critical note is that with these advances, a reconceptualization of the framework in which we view microglia is required. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Background and Purpose: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of Interferon Genes (STING) protein and its downstream type-I Interferon (IFN) signaling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating detrimental neuroinflammatory response after TBI, exacerbating outcome. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. Experimental Approach: This study investigated the neuroprotective effects of the small-molecule STING inhibitor C-176 in the controlled-cortical impact (CCI) mouse model of TBI in 10–12-week-old male mice. 30-minutes post-CCI surgery, a single 750nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2h- and 24h-post TBI. Key Results: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines TNF-α, IL-1β and CXCL10 compared to their vehicle-treated counterparts 2h post-TBI. Conclusion and Implications: This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma induced inflammation and neuroprotective potential.