IL-6 trans-signaling in the brain influences the behavioral and physio-pathological phenotype of the Tg2576 and 3xTgAD mouse models of Alzheimer’s disease

Escrig, Anna; Canal, Carla; Sanchís, Paula; Fernández-Gayol, Olaya; Montilla, Alejandro; Comes, Gemma; Molinero, Amalia; Giralt, Mercedes; Becker‐Pauly, Christoph; Rose–John, Stefan; Hidalgo, Juan

doi:10.1016/j.bbi.2019.08.005

Cited by 28 publications

(26 citation statements)

References 84 publications

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“…Soluble Aβ 40 and Aβ 42 levels were very low (~an order of magnitude below those of Tg2576 mice [32,33]) at an advanced age (2 0 months), in both cortex and hippocampus. Despite the technical difficulties (some mice were below the limit of sensibility of the ELISA), by comparing the present results with those of our earlier study with a control diet [26], we noticed that Aβ levels are further decreased by HFD. The reason for this is unclear, since previous studies do not support such an inhibitory effect of HFD in 3xTg-AD [41,47] and Tg2576 [48].…”

Section: Discussionsupporting

confidence: 69%

“…The parental strains used in this study, GFAP-sgp130Fc and 3xTg-AD mice, were generated and characterized previously [24,27,28]. To obtain the 4 genotypes of interest the following crossing strategy was designed, as in [26]. Homozygous 3xTg-AD (+/+) animals were mated with heterozygous GFAP-sgp130Fc (+/−) to obtain the double transgenic 3xTg-AD/GFAP-sgp130Fc (+/−) (+/−) and 3xTg-AD (+/−) (−/−) mice.…”

Section: Generation Of Double Transgenic 3xtg-ad/gfap-sgp130fc Micementioning

confidence: 99%

“…We hypothesized that blocking IL-6 trans-signaling with sgp130Fc in the brain would impact AD and/or obesity progression. We recently demonstrated the former in two different mouse models of AD, namely the 3xTg-AD mice and the Tg2576 mice, by crossing them with GFAP-sgp130Fc mice in order to obtain 3xTg-AD mice with the IL-6 trans-signaling pathway blocked in the CNS [26]. We herewith present results with 3xTg-AD mice, with and without transgenic sgp130Fc expression by astrocytes, and challenged with a high-fat diet to elicit obesity, which suggest that IL-6 trans-signaling modulates some of the hypermetabolic traits presented by the 3xTg-AD mice in a sex-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s Disease

Escrig

Molinero

Méndez

et al. 2020

Cells

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Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD.

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Section: Discussionsupporting

confidence: 69%

Section: Generation Of Double Transgenic 3xtg-ad/gfap-sgp130fc Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s Disease

Escrig

Molinero

Méndez

et al. 2020

Cells

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“…STAT3 expression remained 15 days after surgery correlating with high glial activation and neuronal death. Besides, the classical IL-6 signaling pathway could induce anti-inflammation and a proinflammatory response by trans-signaling; it has been recently studied because of its implication in neurodegenerative disorders, such as amyloid pathology in AD [ 68 , 69 ]. Cytoplasmic STAT3 expression disappeared on day 15 in controls, but AβO rats exhibited nuclear STAT3 expression in hypertrophic glial cells, correlating with persistent neuronal density reduction.…”

Section: Discussionmentioning

confidence: 99%

Activation of STAT3 Regulates Reactive Astrogliosis and Neuronal Death Induced by AβO Neurotoxicity

Toral-Ríos

Patiño-López

Gómez-Lira

et al. 2020

IJMS

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Amyloid-beta oligomers (AβO) have been proposed as the most potent neurotoxic and inflammation inducers in Alzheimer’s disease (AD). AβO contribute to AD pathogenesis by impairing the production of several cytokines and inflammation-related signaling pathways, such as the Janus kinases/signal transducer of transcription factor-3 (JAK/STAT3) pathway. STAT3 modulates glial activation, indirectly regulates Aβ deposition, and induces cognitive decline in AD transgenic models. However, in vivo studies using an AβO microinjection rat model have not yet explored STAT3 role. The main purpose of this study was to elucidate if a single microinjection of AβO could promote an increased expression of STAT3 in glial cells favoring neuroinflammation and neurodegeneration. We designed a model of intrahippocampal microinjection and assessed glial activation, cytokines production, STAT3 expression, and neurodegeneration in time. Our results showed robust expression of STAT3 in glial cells (mainly in astrocytes) and neurons, correlating with neuronal death in response to AβO administration. A STAT3 inhibition assay conducted in rat primary hippocampal cultures, suggested that the induction of the transcription factor by AβO in astrocytes leads them to an activation state that may favor neuronal death. Notwithstanding, pharmacological inhibition of the JAK2/STAT3 pathway should be focused on astrocytes because it is also essential in neurons survival. Overall, these findings strongly suggest the participation of STAT3 in the development of neurodegeneration.

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“…Several studies on the brain reported that inhibition of IL-6 trans-signaling in microglia and neurons attenuated lipopolysaccharide (LPS)-induced sickness behavior in mice ( Burton et al, 2011 ) and also attenuation of IL-6 trans-signaling mediated neuroinflammation in Alzheimer’s disease models of mice ( Escrig et al, 2019 ). Shi and colleagues reported that elevated IL-6 mRNA levels in activated microglial cells in the PVN contribute to neurogenic hypertension.…”

Section: Il-6 Tnf-α Fkn and Hypertension In The Brainmentioning

confidence: 99%

ADAM17-Mediated Shedding of Inflammatory Cytokines in Hypertension

2020

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The increase of Angiontesin-II (Ang-II), one of the key peptides of the renin-angiotensin system (RAS), and its binding to the Ang-II type 1 receptor (AT 1 R) during hypertension is a crucial mechanism leading to AD\AM17 activation. Among the reported membrane anchored proteins cleaved by ADAM17, immunological cytokines (TNF-a, IFN-g, TGF-b, IL-4, IL-10, IL-13, IL-6, FKN) are the major class of substrates, modulation of which triggers inflammation. The rise in ADAM17 levels has both central and peripheral implications in inflammation-mediated hypertension. This narrative review provides an overview of the role of ADAM17, with a special focus on its cellular regulation on neuronal and peripheral inflammation-mediated hypertension. Finally, it highlights the importance of ADAM17 with regards to the biology of inflammatory cytokines and their roles in hypertension.

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IL-6 trans-signaling in the brain influences the behavioral and physio-pathological phenotype of the Tg2576 and 3xTgAD mouse models of Alzheimer’s disease

Cited by 28 publications

References 84 publications

IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s Disease

IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s Disease

Activation of STAT3 Regulates Reactive Astrogliosis and Neuronal Death Induced by AβO Neurotoxicity

ADAM17-Mediated Shedding of Inflammatory Cytokines in Hypertension

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