Article

IFN- Production by Amyloid -Specific Th1 Cells Promotes Microglial Activation and Increases Plaque Burden in a Mouse Model of Alzheimer's Disease

Trinity College Institute of Neuroscience, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
The Journal of Immunology (Impact Factor: 4.92). 01/2013; 190(5). DOI: 10.4049/jimmunol.1200947
Source: PubMed

ABSTRACT

Alzheimer's disease (AD) is characterized by the presence of amyloid-β (Aβ)-containing plaques, neurofibrillary tangles, and neuronal loss in the brain. Inflammatory changes, typified by activated microglia, particularly adjacent to Aβ plaques, are also a characteristic of the disease, but it is unclear whether these contribute to the pathogenesis of AD or are a consequence of the progressive neurodegenerative processes. Furthermore, the factors that drive the inflammation and neurodegeneration remain poorly understood. CNS-infiltrating T cells play a pivotal role in the pathogenesis of multiple sclerosis, but their role in the progression of AD is still unclear. In this study, we examined the role of Aβ-specific T cells on Aβ accumulation in transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1). We found significant infiltration of T cells in the brains of APP/PS1 mice, and a proportion of these cells secreted IFN-γ or IL-17. Aβ-specific CD4 T cells generated by immunization with Aβ and a TLR agonist and polarized in vitro to Th1-, Th2-, or IL-17-producing CD4(+) T cells, were adoptively transferred to APP/PS1 mice at 6 to 7 mo of age. Assessment of animals 5 wk later revealed that Th1 cells, but not Th2 or IL-17-producing CD4(+) T cells, increased microglial activation and Aβ deposition, and that these changes were associated with impaired cognitive function. The effects of Th1 cells were attenuated by treatment of the APP/PS1 mice with an anti-IFN-γ Ab. Our study suggests that release of IFN-γ from infiltrating Th1 cells significantly accelerates markers of diseases in an animal model of AD.

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    • "Regarding the type II IFN response in AD, it has been previously shown that overexpression of IFN-c boosts the amyloidogenic processing of APP both in vitro and in vivo (Blasko et al., 1999; Mastrangelo et al., 2009). In accordance, it was recently suggested that a higher frequency of IFN-c-producing T-cells in the brain of AD transgenic mice is associated with increased glial activation and amyloid plaque formation , as well as with worst cognitive function (Browne et al., 2013). However, there is also evidence of a beneficial impact of increased levels of IFN-c-producing T-cells in AD transgenic mice at 9 months of age, namely by increased microglial activation, increased Ab phagocytosis and decreased plaque burden in the DG of the HPC (Monsonego et al., 2006 ). "
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a marked decline in cognition and memory function. Increasing evidence highlights the essential role of neuroinflammatory and immune-related molecules, including those produced at the brain barriers, on brain immune surveillance, cellular dysfunction and amyloid beta (Aβ) pathology in AD. Therefore, understanding the response at the brain barriers may unravel novel pathways of relevance for the pathophysiology of AD. Herein, we focused on the study of the choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, in aging and in AD. Specifically, we used the PDGFB-APPSwInd (J20) transgenic mouse model of AD, which presents early memory decline and progressive Aβ accumulation, and littermate age-matched wild-type (WT) mice, to characterize the CP transcriptome at 3, 5-6 and 11-12 months of age. The most striking observation was that the CP of J20 mice displayed an overall overexpression of type I interferon (IFN) response genes at all ages. Moreover, J20 mice presented a high expression of type II IFN genes in the CP at 3 months, which became lower than WT at 5-6 and 11-12 months. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3 months. Altogether, these findings provide new insights on a possible interplay between type I and II IFN responses in AD and point to IFNs as targets for modulation in cognitive decline. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Brain Behavior and Immunity
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    • "The interferon family of cytokines has been shown to be increased in human AD tissue and in the APP/PS1 mouse model, and IFNγ is the main stimulant for microglia to produce an M1 phenotype by binding its receptor, increasing STAT1α, and increasing transcription of several M1 cytokine genes [10,11]. Some studies have used IFNγ to induce an M1 phenotype, with one study showing that classical activation of microglia produces a decrease and another reporting an increase in amyloid burden [12,13]. Other studies have shown that inducing an M1 neuroinflammatory phenotype by introducing TNFα, IL-1β, or lipopolysaccharide (LPS) into the brain lowers amyloid burden [14-17]. "
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    ABSTRACT: Background The polarization to different neuroinflammatory phenotypes has been described in early Alzheimer’s disease, yet the impact of these phenotypes on amyloid-beta (Aβ) pathology remains unknown. Short-term studies show that induction of an M1 neuroinflammatory phenotype reduces Aβ, but long-term studies have not been performed that track the neuroinflammatory phenotype. Methods Wild-type and APP/PS1 transgenic mice aged 3 to 4 months received a bilateral intracranial injection of adeno-associated viral (AAV) vectors expressing IFNγ or green fluorescent protein in the frontal cortex and hippocampus. Mice were sacrificed 4 or 6 months post-injection. ELISA measurements were used for IFNγ protein levels and biochemical levels of Aβ. The neuroinflammatory phenotype was determined through quantitative PCR. Microglia, astrocytes, and Aβ levels were assessed with immunohistochemistry. Results AAV expressing IFNγ induced an M1 neuroinflammatory phenotype at 4 months and a mixed phenotype along with an increase in Aβ at 6 months. Microglial staining was increased at 6 months and astrocyte staining was decreased at 4 and 6 months in mice receiving AAV expressing IFNγ. Conclusions Expression of IFNγ through AAV successfully induced an M1 phenotype at 4 months that transitioned to a mixed phenotype by 6 months. This transition also appeared with an increase in amyloid burden suggesting that a mixed phenotype, or enhanced expression of M2a and M2c markers, could contribute to increasing amyloid burden and disease progression.
    Full-text · Article · Jul 2014 · Journal of Neuroinflammation
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    • "Furthermore, inflammatory IFNγ-secreting Th1 cells and IL-17-secreting Th17 cells have been shown to infiltrate the brain of older APP/PS1 mice [107], supporting the observation of infiltrating T cells in the brain of AD patients [108]. However, the role of these cells in the AD brain is still unknown. "
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    ABSTRACT: Over the past decade the process of inflammation has been a focus of increasing interest in the Alzheimer's disease (AD) field, not only for its potential role in neuronal degeneration but also as a promising therapeutic target. However, recent research in this field has provided divergent outcomes, largely due to the use of different models and different stages of the disease when the investigations have been carried out. It is now accepted that microglia, and possibly astrocytes, change their activation phenotype during ageing and the stage of the disease, and therefore these are important factors to have in mind to define the function of different inflammatory components as well as potential therapies. Modulating inflammation using animal models of AD has offered the possibility to investigate inflammatory components individually and manipulate inflammatory genes in amyloid precursor protein and tau transgenics independently. This has also offered some hints on the mechanisms by which these factors may affect AD pathology. In this review we examine the different transgenic approaches and treatments that have been reported to modulate inflammation using animal models of AD. These studies have provided evidence that enhancing inflammation is linked with increases in amyloid-beta (Abeta) generation, Abeta aggregation and tau phosphorylation. However, the alterations on tau phosphorylation can be independent of changes in Abeta levels by these inflammatory mediators.
    Full-text · Article · Feb 2014 · Journal of Neuroinflammation
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