Telomere dysfunction reduces microglial numbers without fully inducing an aging phenotype

Khan, Asif Iqbal; Babcock, Alicia; Saeed, Hamid; Myhre, Christa Løth; Kassem, Moustapha; Finsen, Bente

doi:10.1016/j.neurobiolaging.2015.03.008

Cited by 22 publications

(26 citation statements)

References 69 publications

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“…In adult mice about 1% of microglia proliferate over a period of 24 h (Wirenfeldt et al, ), but they neither exhibit the morphology observed in AD brains nor the induction of CD68 and ferritin during aging (28 months). This is also true for mice lacking the telomerase RNA component (Khan et al, ). There is also data supporting the view that immune senescence is a more systemic feature of AD (Gonzàlez and Pacheco, 2010; Streit and Xue, ; Wang et al, ).…”

Section: Discussionmentioning

confidence: 89%

Inhomogeneous distribution of Iba‐1 characterizes microglial pathology in Alzheimer's disease

Tischer

Krueger

Mueller

et al. 2016

Glia

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Microglial dystrophy has recently been described as a morphological phenotype of microglia that differs from resting and activated states by spheroid formation and cytorrhexis. In thick sections immunolabeled for HLA-DR or Iba-1 dystrophic microglial processes lose their typical, homogeneous staining pattern and appear to be fragmented or clustered. In this study, we performed double immunofluorescence and electron microscopy to determine if this labeling pattern indeed reflects complete separation of microglial processes from the soma. Using Iba-1/CD68 and Iba-1/MHC class II, as microglial markers, we observed that isolated Iba-1 fragments were still connected to each other by segments of the microglial process immune positive for CD68 or MHC class II. Ultrathin serial sections of two Iba-1 fragments which appeared to be disconnected from each other at the light microscopical level revealed a still existing "bridge" with a diameter of around 0.182 µm. Therefore, microglial dystrophy may reflect alterations of the cytoskeleton ultimately leading to slow cytorrhexis. GLIA 2016;64:1562-1572.

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Section: Discussionmentioning

confidence: 89%

Inhomogeneous distribution of Iba‐1 characterizes microglial pathology in Alzheimer's disease

Tischer

Krueger

Mueller

et al. 2016

Glia

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“… Data from immunoblots of mitochondrial protein subunit expression ( A ), CREB, p-CREB, MAPK and p-MAPK ( C ) as well as PKA and PKC motif immunoblotting ( E ) are depicted from 0 ng/ml, 0.1 ng/ml, 1.0 ng/ml and 10.0 ng/ml TNFα stimulation over 24 hours in HT22 cells. The columns represent the fold-changes with standard errors of the mean [ 67 ]; n = 3; * p < 0.05; ** p < 0.01; *** p < 0.001 (unpaired Student s t -test). Normalization was performed against endogenous GAPDH for mitochondrial proteins as well as PKA and PKC motif immunoblotting; CREB, p-CREB, MAPK and p-MAPK were normalized against total lane intensity via Ponceau S staining.…”

Section: Resultsmentioning

confidence: 99%

TNFα affects CREB-mediated neuroprotective signaling pathways of synaptic plasticity in neurons as revealed by proteomics and phospho-proteomics

et al. 2017

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Neuroinflammation is a hallmark of Alzheimer's disease and TNFα as the main inducer of neuroinflammation has neurodegenerative but also pro-regenerative properties, however, the dose-dependent molecular changes on signaling pathway level are not fully understood. We performed quantitative proteomics and phospho-proteomics to target this point.In HT22 cells, we found that TNFα reduced mitochondrial signaling and inhibited mTOR protein translation signaling but also led to induction of neuroprotective MAPK-CREB signaling. Stimulation of human neurons with TNFα revealed similar cellular mechanisms. Moreover, a number of synaptic plasticity-associated genes were altered in their expression profile including CREB.SiRNA-mediated knockdown of CREB in human neurons prior to TNFα stimulation led to a reduced number of protein/phospho-protein hits compared to siRNA-mediated knockdown of CREB or TNFα stimulation alone and countermeasured the reduced CREB signaling. In vivo data of TNFα knockout mice showed that learning ability did not depend on TNFα per se but that TNFα was essential for preserving the learning ability after episodes of lipopolysaccharide-induced neuroinflammation. This may be based on modulation of CREB/CREB signaling as revealed by the in vitro / in vivo data.Our data show that several molecular targets and signaling pathways induced by TNFα in neurons resemble those seen in Alzheimer's disease pathology.

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“…Microglia from aged mice are known to express higher levels of inflammatory mediators and cytokines than microglia from young mice (Godbout et al, 2005;Hickman et al, 2013;Lynch et al, 2010;Sierra et al, 2007). Analysis of the microglial sensome with age revealed selective downregulation of transcripts used for detecting endogenous damage (Hickman et al, 2013), consistent with changes in microglial morphology, distribution and reduced surveillance coverage in aged mice (Baron et al, 2014;Hefendehl et al, 2014;Khan et al, 2015). Microglia may become primed with age, and sensitized to immune challenges or Ab accumulation (Dilger and Johnson, 2008;Godbout et al, 2005;Perry et al, 2007).…”

Section: Discussionmentioning

confidence: 95%

Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice

Babcock¹,

Ilkjær

Clausen³

et al. 2015

Brain, Behavior, and Immunity

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102

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Telomere dysfunction reduces microglial numbers without fully inducing an aging phenotype

Cited by 22 publications

References 69 publications

Inhomogeneous distribution of Iba‐1 characterizes microglial pathology in Alzheimer's disease

Inhomogeneous distribution of Iba‐1 characterizes microglial pathology in Alzheimer's disease

TNFα affects CREB-mediated neuroprotective signaling pathways of synaptic plasticity in neurons as revealed by proteomics and phospho-proteomics

Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice

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