Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer's disease

Jm, Taylor; Minter, Myles R.; Newman, Andrew G.; Zhang, Moses; Adlard, Paul A.; Crack, Peter J

doi:10.1016/j.neurobiolaging.2013.10.089

Cited by 125 publications

(148 citation statements)

References 36 publications

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“…This effect of IFN-b on neuronal excitability 760 was shown to be mediated by IFNAR1, due to the lack of changes in 761 the HPC of Ifnra1-null mice (Costello and Lynch, 2013). 762 Additionally, 9 months-old transgenic APP/PS1 mice present 763 higher levels of IFN-a in the brain, when compared to 764 age-matched WT mice (Taylor et al, 2014). Interestingly, our 765 results also suggest that, along with a possible impact on behavior, …”

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confidence: 67%

“…Scale bar indicates 100 lm in (H). 715 pathogenesis(Baruch et al, 2014; Scholtzova et al, 2009 Scholtzova et al, , 2014 716Taylor et al, 2014). Regarding the type II IFN response in AD, it 717 has been previously shown that overexpression of IFN-c boosts 718 the amyloidogenic processing of APP both in vitro and in vivo 719(Blasko et al, 1999;Mastrangelo et al, 2009).…”

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confidence: 99%

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The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer’s disease

Mesquita

Ferreira

Gao

et al. 2015

Brain, Behavior, and Immunity

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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 11-12months 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 3months, which became lower than WT at 5-6 and 11-12months. 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 3months. 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.

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confidence: 67%

mentioning

confidence: 99%

The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer’s disease

Mesquita

Ferreira

Gao

et al. 2015

Brain, Behavior, and Immunity

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“…For example, the capacity of ␤-catenin to modulate inflammatory and immune responses (71) could be related to its ability to modulate the expression of IFN-␤, which is a major regulator of immunity and inflammatory responses. Also, cross talk between ␤-catenin and IFN-␤ during the establishment and/or treatment of neurological disorders, such as Alzheimer's disease and multiple sclerosis, should be considered, since both the Wnt/␤-catenin pathway and the IFN-␤ response have been associated with these neurological pathologies (72)(73)(74). Although modulation of the constitutive level of IFN-␤ expression has probably been observed in the past by many researchers, it has often been neglected because it seemed to be only a minor response compared to pathogen-induced IFN-␤ expression.…”

Section: Licl Treatment Enhances Constitutive Ifn-␤ Gene Expressionmentioning

confidence: 99%

β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

Marcato

Luron

Laqueuvre

et al. 2016

Molecular and Cellular Biology

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. Rapid upregulation of IFN-␤ gene expression occurs after recognition of viral nucleic acids by pattern recognition receptors (PRRs) consisting of either cytosolic receptors, such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5), or membrane-associated Toll-like receptors, such as Toll-like receptor 3 (TLR3) (3). After sensing single-or doublestranded RNA of viral origin, these receptors activate signaling pathways, implicating the phosphorylation and nuclear translocation of several transcription factors, among which is interferon regulatory factor 3 (IRF3), rapidly leading downstream to a robust activation of expression of the IFN-␤ gene. After being secreted, the IFN-␤ protein binds to the type I interferon receptor and triggers the JAK-STAT1/2 signal transduction pathway. This pathway leads to the activation and inhibition of the expression of a large set of genes that constitute the type I IFN response mounted to antagonize viral infection at different levels (4).Mice lacking IFN-␤ (5) or the subunit of the type I interferon receptor (6, 7) are highly susceptible to viral infections. They succumb to sublethal doses of a variety of viruses, thus confirming the main role of IFN-␤ in the establishment of an innate antiviral response. However, beyond the antiviral response, IFN-␤ affects a wide range of other biological functions; for the most part, these are related to modulation of the immune (innate and adaptive) and inflammatory responses as well as to cell proliferation and differentiation. Even though IFN-␤ has been described to have an anti-inflammatory benefit, it has also been implicated in the development of several inflammatory and autoimmune diseases (8-10). Hence, the beneficial or detrimental outcome of IFN-␤ expression for the organism depends on the timing and kinetics of IFN-␤ synthesis and the amount of IFN-␤ being synthesized (11,12). If a marked activation of IFN-␤ gene expression is required to efficiently set up the appropriate response to an external aggression, such as virus infection, this response needs to be adjusted in order to limit its pathological side effects.As expected for a gene with pleiotropic functions, its transcriptional state is regulated at different levels. At the cellular level, only a stochastic fraction of the infected cells produces 14) as a way to avoid an exacerbated and uncontrolled IFN response. At the nuclear level, one IFN-␤ allele localizes within interchromosomal regions rich in NF-B DNA binding sites before and after infection (15), whereas the other allele localizes next to pericentromeric heterochromatin (PCH) clusters in the absence of infection and dissociates from PCH clusters during infection (16). The monoallelic characteristic of these particular subnuclear localizations suggests that a yet undeciphered regulatory mechanism exists at the chromosome level. Finally, at the promoter level, the coordinated action of several transcription factors and chromatin-remodeling complexes (17-21) regulates the...

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“…Mixed cortical and hippocampal neurons were isolated from embryos on embryonic day 14-16, as previously described [17]. Cells were maintained in Dulbecco’s modified Eagle’s medium (D-MEM; Nacalai tesque, Kyoto, Japan) containing 10% foetal bovine serum, 100 units/mL penicillin, and 100 µg/mL streptomycin in a humidified atmosphere of 95% air and 5% CO 2 at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Cell viability was measured by the cellular ability to metabolize MTS (Promega Corporation, Madison, USA) in the presence of phenazine methosulfate to a formazan product, as described previously [17]. The results were expressed as a percentage of the absorbance at 490 nm of the control vehicle.…”

Section: Methodsmentioning

confidence: 99%

TRPML1 Participates in the Progression of Alzheimer’s Disease by Regulating the PPARγ/AMPK/Mtor Signalling Pathway

Zhang

Fang

Chen

et al. 2017

Cell Physiol Biochem

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Background: TRPML1 is reported to be involved in the pathogenesis of Alzheimer’s disease (AD) by regulating autophagy; however, the underlying mechanism is not completely clear. Methods: We developed an APP/PS1 transgenic animal model that presents with AD. TRPML1 was also overexpressed in these mice. Protein expression levels were determined by Western blot. Morris water maze (MWM) and recognition tasks were performed to characterize cognitive ability. TUNEL assays were analysed for the detection of neuronal apoptosis. Primary neurons were isolated and treated with the vehicle, Aβ1-42 or Aβ1-42 + mTOR activator, as well as infected with the recombinant adenovirus TRPML1 overexpression vector in vitro. Cell viability was measured by the MTS assay, and lysosomal Ca²⁺ was also measured. Results: In the APP/PS1 transgenic mice, TRPML1 was downregulated, the PPARγ/AMPK signalling pathway was activated, the mTOR/S6K signalling pathway was suppressed, and autophagic lysosome reformation (ALR)-related proteins were upregulated. TRPML1 overexpression or treatment with PPARγ and AMPK inhibitors or an mTOR activator reduced the expression levels of ALR-related proteins, rescued the memory and recognition impairments and attenuated neuronal apoptosis in mice with the APP/PS1 transgenes. In vitro experiments showed that TRPML1 overexpression or treatment with the mTOR activator propranolol attenuated the Aβ1-42-suppressed cell viability and the Aβ1-42-decreased lysosomal [Ca²⁺] ion concentration in primary neurons. TRPML1 overexpression or treatment with the mTOR activator propranolol also attenuated the Aβ1-42-inhibited mTOR/S6K signalling pathway and the Aβ1-42-induced ALR-related protein expression levels. Conclusion: TRPML1 is involved in the pathogenesis of AD by regulating autophagy at least in part through the PPARγ/AMPK/mTOR signallingpathway.

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Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer's disease

Cited by 125 publications

References 36 publications

The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer’s disease

The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer’s disease

β-Catenin Upregulates the Constitutive and Virus-Induced Transcriptional Capacity of the Interferon Beta Promoter through T-Cell Factor Binding Sites

TRPML1 Participates in the Progression of Alzheimer’s Disease by Regulating the PPARγ/AMPK/Mtor Signalling Pathway

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