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排序方式: 共有143条查询结果,搜索用时 296 毫秒
21.
Susanne Wegmann Eduardo A Maury Molly J Kirk Lubna Saqran Allyson Roe Sarah L DeVos Samantha Nicholls Zhanyun Fan Shuko Takeda Ozge Cagsal‐Getkin Christopher M William Tara L Spires‐Jones Rose Pitstick George A Carlson Amy M Pooler Bradley T Hyman 《The EMBO journal》2015,34(24):3028-3041
In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion‐like mechanism has been suggested: misfolded tau propagating through the brain seeds neurotoxic aggregation of soluble tau in recipient neurons. We use transgenic mice and viral tau expression to test the hypotheses that trans‐synaptic tau propagation, aggregation, and toxicity rely on the presence of endogenous soluble tau. Surprisingly, mice expressing human P301Ltau in the entorhinal cortex showed equivalent tau propagation and accumulation in recipient neurons even in the absence of endogenous tau. We then tested whether the lack of endogenous tau protects against misfolded tau aggregation and toxicity, a second prion model paradigm for tau, using P301Ltau‐overexpressing mice with severe tangle pathology and neurodegeneration. Crossed onto tau‐null background, these mice had similar tangle numbers but were protected against neurotoxicity. Therefore, misfolded tau can propagate across neural systems without requisite templated misfolding, but the absence of endogenous tau markedly blunts toxicity. These results show that tau does not strictly classify as a prion protein. 相似文献
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Degryse AL Tanjore H Xu XC Polosukhin VV Jones BR Boomershine CS Ortiz C Sherrill TP McMahon FB Gleaves LA Blackwell TS Lawson WE 《American journal of physiology. Lung cellular and molecular physiology》2011,300(6):L887-L897
The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice that express β-galactosidase (β-gal) in cells of lung epithelial lineage. Mice were given intratracheal bleomycin (0.08 U), and the following parameters were assessed: AEC death by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, inflammation by total and differential cell counts from bronchoalveolar lavage, fibrosis by scoring of trichrome-stained lung sections, and total lung collagen content. Mice with lung epithelial deficiency of TGFβR2 had improved AEC survival, despite greater lung inflammation, after bleomycin administration. At 3 wk after bleomycin administration, mice with epithelial TGFβR2 deficiency showed a significantly attenuated fibrotic response in the lungs, as determined by semiquantitatve scoring and total collagen content. The reduction in lung fibrosis in these mice was associated with a marked decrease in the lung fibroblast population, both total lung fibroblasts and epithelial-to-mesenchymal transition-derived (S100A4(+)/β-gal(+)) fibroblasts. Attenuation of TGFβ signaling in lung epithelium provides protection from bleomycin-induced fibrosis, indicating a critical role for the epithelium in transducing the profibrotic effects of this cytokine. 相似文献
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Neurodegenerative disorders, such as Huntington's, Alzheimer's, and Parkinson's diseases, affect millions of people worldwide and currently there are few effective treatments and no cures for these diseases. Transgenic mice expressing human transgenes for huntingtin, amyloid precursor protein, and other genes associated with familial forms of neurodegenerative disease in humans provide remarkable tools for studying neurodegeneration because they mimic many of the pathological and behavioural features of the human conditions. One of the recurring themes revealed by these various transgenic models is that different diseases may share similar molecular and cellular mechanisms of pathogenesis. Cellular mechanisms known to be disrupted at early stages in multiple neurodegenerative disorders include gene expression, protein interactions (manifesting as pathological protein aggregation and disrupted signaling), synaptic function and plasticity. Recent work in mouse models of Huntington's disease has shown that enriching the environment of transgenic animals delays the onset and slows the progression of Huntington's disease-associated motor and cognitive symptoms. Environmental enrichment is known to induce various molecular and cellular changes in specific brain regions of wild-type animals, including altered gene expression profiles, enhanced neurogenesis and synaptic plasticity. The promising effects of environmental stimulation, demonstrated recently in models of neurodegenerative disease, suggest that therapy based on the principles of environmental enrichment might benefit disease sufferers and provide insight into possible mechanisms of neurodegeneration and subsequent identification of novel therapeutic targets. Here, we review the studies of environmental enrichment relevant to some major neurodegenerative diseases and discuss their research and clinical implications. 相似文献
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Targeted immunomodulation of the NF-kappaB pathway in airway epithelium impacts host defense against Pseudomonas aeruginosa 总被引:1,自引:0,他引:1
Sadikot RT Zeng H Joo M Everhart MB Sherrill TP Li B Cheng DS Yull FE Christman JW Blackwell TS 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(8):4923-4930
We investigated the impact of inflammatory signaling in airway epithelial cells on host defense against Pseudomonas aeruginosa, a major cause of nosocomial pneumonia. In mice, airway instillation of P. aeruginosa resulted in NF-kappaB activation in the lungs that was primarily localized to the bronchial epithelium at 4 h, but was present in a variety of cell types by 24 h. We modulated NF-kappaB activity in airway epithelium by intratracheal delivery of adenoviral vectors expressing RelA (AdRelA) or a dominant inhibitor of NF-kappaB before P. aeruginosa infection. Bacterial clearance was enhanced by up-regulation of NF-kappaB activity following AdRelA administration and was impaired by treatment with a dominant inhibitor of NF-kappaB. The TNF-alpha concentration in lung lavage was increased by AdRelA treatment and beneficial effects of NF-kappaB up-regulation were abrogated in TNF-alpha-deficient mice. In contrast, NF-kappaB inhibition reduced MIP-2 expression and neutrophil influx following P. aeruginosa infection. Therefore, inflammatory signaling through the NF-kappaB pathway in airway epithelial cells critically regulates the innate immune response to P. aeruginosa. 相似文献
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Peripheral blood lymphocytes from cattle, pigs, sheep and humans were cultured in the presence of 0.5, 1, 2, 5, 10 or 20 micrograms/ml of BrdUrd. Sister-chromatid exchanges were scored in 25 second-division metaphases from each donor at each level of the chemical. Dose--response curves for all 4 species increased steeply to 2 micrograms/ml; above this level, SCE numbers increased less rapidly but maintained a linear relationship to increasing BrdUrd concentration. Comparisons of the straight-line portions of the dose--response curves showed human cells to be significantly more sensitive to increasing BrdUrd level than cow or pig cells and different from sheep at the 10% level of confidence. 相似文献
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The preceding paper showed that those conditions that ought to stimulate reacylation of lysolipids in cells can increase cell adhesions. Similarly we found that conditions that would be expected to lead to the accumulation of lysolipids in the cell surface diminish cell adhesion. This paper reports on the answers to the following questions. (1) Is reacylation of lysolipids in the cells stimulated by an external supply of CoA, ATP and a fatty acid? (2) Does this reacylation lead to the incorporation of exogenous fatty acid in the plasmlemma? (3) What range of fatty acids can be incorporated into the plasmalemma and into what compounds? (4) Does the plasmalemma contain the enzyme systems to effect this turnover, namely phospholipase A2, a CoA-ligase and an appropriate acyl transferase(s)? (5) Do lysolipids accumulate in the plasmalemma under conditions which diminish cell adhesion? We find that saturated fatty acids in the range C14--C18, and some unsaturated fatty acids are incorporated into the plasmalemmae of these neural retina cells. About 20% of the plasmlemma content of fatty acids can be turned over in 30'. Incorporation is mainly into phosphatidyl choline, serine and ethanolamine in both R1 and R2 positions. The plasmalemmae contain the enzymes to effect the turnover. Isolated plasmalemmae are active in this turnover. Incubation of the plasmalemmae with phospholipase A2 leads to an accumulation of lysolipids. Very low levels of phospholipase stimulate turnover, possibly endogenous phospholipase activity is the rate-limiting step in the system. These findings are discussed in relation to the possible mechanisms by which lipids might affect adhesion. 相似文献
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