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21.
Lithium is an anti-psychotic that has been shown to prevent the hyperphosphorylation of tau protein through the inhibition of glycogen-synthase kinase 3-beta (GSK3β). We recently developed a mouse model that progresses from amyloid pathology to tau pathology and neurodegeneration due to the genetic deletion of NOS2 in an APP transgenic mouse; the APPSwDI/NOS2-/- mouse. Because this mouse develops tau pathology, amyloid pathology and neuronal loss we were interested in the effect anti-tau therapy would have on amyloid pathology, learning and memory. We administered lithium in the diets of APPSwDI/NOS2-/- mice for a period of eight months, followed by water maze testing at 12 months of age, immediately prior to sacrifice. We found that lithium significantly lowered hyperphosphorylated tau levels as measured by Western blot and immunocytochemistry. However, we found no apparent neuroprotection, no effect on spatial memory deficits and an increase in histological amyloid deposition. Aβ levels measured biochemically were unaltered. We also found that lithium significantly altered the neuroinflammatory phenotype of the brain, resulting in enhanced alternative inflammatory response while concurrently lowering the classical inflammatory response. Our data suggest that lithium may be beneficial for the treatment of tauopathies but may not be beneficial for the treatment of Alzheimer's disease. 相似文献
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Targeting of an Intestinal Apical Endosomal Protein to Endosomes in Nonpolarized Cells 总被引:4,自引:2,他引:2 下载免费PDF全文
Polarized cells such as epithelial cells and neurons have distinct endosomal compartments associated with different plasma membrane domains. The endosomes of the neuronal cell body and the basolateral cytoplasm of epithelial cells are thought to perform cellular “housekeeping” functions such as the uptake of nutrients and metabolites, while the endosomes in the apical cytoplasm or axons are thought to be specialized for the sorting and transcytosis of cell type–specific ligands and receptors. However, it is not known if nonpolarized cells such as fibroblasts contain a specialized endosomal compartment analogous to the specialized endosomes found in neurons and epithelia. We have expressed a protein that is normally found in the apical early endosomes of developing intestinal epithelial cells in normal rat kidney fibroblasts. This apical endosomal marker, called endotubin, is targeted to early endosomes in transfected fibroblasts, and is present in peripheral as well as perinuclear endosomes. The peripheral endosomes that contain endotubin appear to exclude transferrin, fluid phase markers, and the mannose-6-phosphate receptor, although in the perinuclear region colocalization of endotubin and these markers is present. In addition, endotubin positive structures do not tubulate in response to brefeldin A and instead redistribute to a diffuse perinuclear location. Since this endosomal compartment has many of the characteristics of an apical or axonal endosomal compartment, our results indicate that nonpolarized cells also contain a specialized early endosomal compartment. 相似文献
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James T. Kelley Robert Everett Edward L. Reilly Glenn S. Colton 《Bioelectromagnetics》1984,5(4):365-375
Pilot studies demonstrate evidence that the electrophysiological processes associated with flash stimulation of the central nervous system (CNS) of rats, as seen in the recordings of visual-evoked potentials, may also be detectable using an ultrahigh frequency electromagnetic field (UHFEMF). Patterns of amplitude modulation of an applied UHFEMF, when recorded and averaged, show strong correlations with simultaneously recorded evoked potentials. The data support the hypothesis that the UHFEMF amplitude is altered in a dynamic fashion by the tissue's electrophysiological processes that are involved with the generation of CNS electric fields. 相似文献
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Colton Linnertz Laura Saucier Dongliang Ge Kenneth D. Cronin James R. Burke Jeffrey N. Browndyke Christine M. Hulette Kathleen A. Welsh-Bohmer Ornit Chiba-Falek 《PloS one》2009,4(10)
Genetic variability across the SNCA locus has been repeatedly associated with susceptibility to sporadic Parkinson''s disease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. However whether genetic variability in the SNCA gene modulates the risk to develop sporadic PD via regulation of SNCA expression remained elusive. We studied the effect of PD risk-associated variants at SNCA 5′ and 3′regions on SNCA-mRNA levels in vivo in 228 human brain samples from three structures differentially vulnerable to PD pathology (substantia-nigra, temporal- and frontal-cortex) obtained from 144 neurologically normal cadavers. The extensively characterized PD-associated promoter polymorphism, Rep1, had an effect on SNCA-mRNA levels. Homozygous genotype of the ‘protective’, Rep1-259 bp allele, was associated with lower levels of SNCA-mRNA relative to individuals that carried at least one copy of the PD-risk associated alleles, amounting to an average decrease of ∼40% and >50% in temporal-cortex and substantia-nigra, respectively. Furthermore, SNPs tagging the SNCA 3′-untranslated-region also showed effects on SNCA-mRNA levels in both the temporal-cortex and the substantia-nigra, although, in contrast to Rep1, the ‘decreased-risk’ alleles were correlated with increased SNCA-mRNA levels. Similar to Rep1 findings, no difference in SNCA-mRNA level was seen with different SNCA 3′SNP alleles in the frontal-cortex, indicating there is brain-region specificity of the genetic regulation of SNCA expression. We provide evidence for functional consequences of PD-associated SNCA gene variants in disease relevant brain tissues, suggesting that genetic regulation of SNCA expression plays an important role in the development of the disease. 相似文献
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Over the last two decades there as has been surging scientific interest in employing the glucose- and mannose-specific lectin Concanavalin A (ConA) in affinity biosensors for in vivo glucose monitoring in diabetics. Numerous research groups have successfully shown in in vitro and in vivo studies that ConA-based affinity sensors can monitor glucose very accurately and reproducibly over many months, making ConA-based sensors an extremely interesting prospect for long-term implantation in humans. Despite this progress, there remains concern over the safety of ConA, which has widely been reported as a toxin in the literature. In this article, we review in vitro and in vivo studies related to ConA toxicity in order to assess the health risks posed by ConA in the context of an implantable biosensor. Based on the wealth of information available and on data from our own studies, we can conclude that the site of implantation (subcutaneous skin tissue) and the small amount of ConA (<10 microg/microl) being used in implantable glucose-sensitive detector devices like those proposed by various research groups would pose little or no health risk to its bearer even in the event of unexpected sensor rupture. 相似文献
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Rory S. Telemeco Brooke Fletcher Ofir Levy Angela Riley Yesenia Rodriguez‐Sanchez Colton Smith Collin Teague Amanda Waters Michael J. Angilletta Jr Lauren B. Buckley 《Global Change Biology》2017,23(3):1075-1084
Although observations suggest the potential for phenotypic plasticity to allow adaptive responses to climate change, few experiments have assessed that potential. Modeling suggests that Sceloporus tristichus lizards will need increased nest depth, shade cover, or embryonic thermal tolerance to avoid reproductive failure resulting from climate change. To test for such plasticity, we experimentally examined how maternal temperatures affect nesting behavior and embryonic thermal sensitivity. The temperature regime that females experienced while gravid did not affect nesting behavior, but warmer temperatures at the time of nesting reduced nest depth. Additionally, embryos from heat‐stressed mothers displayed increased sensitivity to high‐temperature exposure. Simulations suggest that critically low temperatures, rather than high temperatures, historically limit development of our study population. Thus, the plasticity needed to buffer this population has not been under selection. Plasticity will likely fail to compensate for ongoing climate change when such change results in novel stressors. 相似文献
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Bose JL Wollenberg MS Colton DM Mandel MJ Septer AN Dunn AK Stabb EV 《Applied and environmental microbiology》2011,77(7):2445-2457