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

Browne, Tara C.; McQuillan, Keith; McManus, Róisín M.; O’Reilly, Julie-Ann; Mills, Kingston H. G.; Lynch, Marina A.

doi:10.4049/jimmunol.1200947

Cited by 246 publications

(194 citation statements)

References 66 publications

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“…Another inflammatory cytokine that apparently aggravates AD is IFN-γ, i.e. Aβ-specific CD4+ Th1 cells adoptively transferred to an AD mouse model increased microglia activation and Aβ deposition, effects that were attenuated with an IFN-γ antibody (27). Yet, this study showed that while Th2 cells had beneficial effects, the Th17 cells did not cause damage, despite being strongly inflammatory.…”

Section: Rev Neuropsiquiatr 78 (3) 2015contrasting

confidence: 44%

Alzheimer’s disease: Toward the rational design of an effective vaccine.

Marciani¹

2015

Rev Neuropsiquiatr

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The promising clinical results with the human monoclonal antibodies aducanumab and solanezumab targeting β-amyloidin Alzheimer’s disease treatment, confirm both the amyloid cascade hypothesis and protective natural immunity, while strengthening the immunotherapeutic approach. That aducanumab recognizes a conformational epitope formed by oligomers emphasizes the need for whole β-amyloid, not just its B-cell epitopes as have been the norm to avoid pro-inflammatory Th1-reactions. That truncated β-amyloid having N-terminal pyroglutamate is present only in diseased brain simplies a new useful vaccine antigen. Another relevant antigen is the tau protein, which shows a close association and cooperativity with β-amyloid in exacerbating this disease. Hence, effective vaccines may be polyvalent, presenting to the immune system a number of antigens relevant to induce an immune response to prevent or slowdown the onset of this disease. The presence of both B and T cell epitopes in the antigens, require a sole Th2 immunity to avert brain inflammation; a task that cannot be attain with adjuvants that under any conditions induce Th1and/or Th17immunities.Hence, new vaccine adjuvants are need to safely induce Th2 while inhibiting Th1 immunity, an objective that can be achieved with certain fucosylated glycans or triterpene glycosides, which apparently bind to the DC-SIGN lectin on dendritic cells polarizing the immune response toward Th2 immunity. Because the triterpene glycosides have the pharmacophore needed to co-stimulate T cells, they may ameliorate the T-cell anergy associated with immunosenescence and responsible for poor vaccine efficacy in theelderly population, a critical issue for an Alzheimer’s vaccine.

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Section: Rev Neuropsiquiatr 78 (3) 2015contrasting

confidence: 44%

Alzheimer’s disease: Toward the rational design of an effective vaccine.

Marciani¹

2015

Rev Neuropsiquiatr

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“…Further, the stimulation of Ab-reactive T cells at sites of Ab plaques resulted in IFNc-induced chemotaxis of leukocytes and therapeutic clearance of Ab (Fisher et al 2010). In contrast, recent data indicate that IFN-c produced by T-cells infiltrating the brain in AD tend to elevate microglial activation, Ab deposition and impaired cognitive functions, and these effects were ameliorated by systemic administration of anti-IFN-c antibody in mice with AD (Browne et al 2013).…”

Section: Microglia In Ad Brainsmentioning

confidence: 89%

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

et al. 2015

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Alzheimer's disease (AD) is the most common form of dementia. It is characterized by beta-amyloid (Aβ) peptide fibrils, which are extracellular depositions of a specific protein, and is accompanied by extensive neuroinflammation. Various studies have demonstrated risk factors that can affect AD pathogenesis, and they include accumulation of Aβ, hyperphosphorylation of tau protein, and neuroinflammation. Among these detrimental factors, neuroinflammation has been highlighted by epidemiologic studies suggesting that use of anti-inflammatory drugs could significantly reduce the incidence of AD. Evidence suggests that astrocytes, microglia, and infiltrating immune cells from periphery might contribute to or modify the process of neuroinflammation and neurodegeneration in AD brains. In addition, recent data indicate that microRNAs may affect neuroinflammatory responses in the brain. This article focuses on supportive evidence that neuroinflammation plays a critical role in AD development. In addition, we depict putative therapeutic capacity of anti-inflammatory drugs for AD prevention or treatment. We also discuss pathogenic mechanisms by which astrocytes, microglia, T cells and microRNA participate in AD and the neuroprotective mechanisms of anti-inflammatory drugs.

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“…To evaluate the impact of MCC950 in a model of AD, APP/PS1 mice were treated for 3 months from 12 months, an age at which cognitive changes are evident (Browne et al, 2013) and Aβ plaques are well developed. We show that MCC950 attenuated the genotype-related deficits in 2 tests of cognition, and that this was accompanied by a reduction in Aβ plaque numbers and soluble Aβ concentration reflecting the ability of MCC950 to increase phagocytosis of Aβ.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice

Dempsey

Rubio-Araiz

Bryson

et al. 2017

Brain, Behavior, and Immunity

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., Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice, Brain, Behavior, and Immunity (2016), doi: http://dx.doi.org/10. 1016/j.bbi.2016.12.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impacts on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Aβ-induced caspase 1 activation in microglia and this was accompanied by IL-1β release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aβ phagocytosis in vitro, and it reduced Aβ accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function.

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

Cited by 246 publications

References 66 publications

Alzheimer’s disease: Toward the rational design of an effective vaccine.

Alzheimer’s disease: Toward the rational design of an effective vaccine.

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice

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