The CCAAT/enhancer binding protein (C/EBP) δ is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-β peptide

<p>Abstract</p> <p>Background</p> <p>The transcription factors CCAAT/enhancer binding proteins (C/EBP) α, β and δ have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor κB (NF-κB). In general, C/EBPα is down-regulated, whereas both C/EBPβ and δ are up-regulated in response to inflammatory stimuli. In Alzheimer's disease (AD) one of the hallmarks is chronic neuroinflammation mediated by astrocytes and microglial cells, most likely induced by the formation of amyloid-β (Aβ) deposits. The inflammatory response in AD has been ascribed both beneficial and detrimental roles. It is therefore important to delineate the inflammatory mediators and signaling pathways affected by Aβ deposits with the aim of defining new therapeutic targets.</p> <p>Methods</p> <p>Here we have investigated the effects of Aβ on expression of C/EBP family members with a focus on C/EBPδ in rat primary astro-microglial cultures and in a transgenic mouse model with high levels of fibrillar Aβ deposits (tg-ArcSwe) by western blot analysis. Effects on DNA binding activity were analyzed by electrophoretic mobility shift assay. Cross-talk between C/EBPδ and NF-κB was investigated by analyzing binding to a κB site using a biotin streptavidin-agarose pull-down assay.</p> <p>Results</p> <p>We show that exposure to fibril-enriched, but not oligomer-enriched, preparations of Aβ inhibit up-regulation of C/EBPδ expression in interleukin-1β-activated glial cultures. Furthermore, we observed that, in aged transgenic mice, C/EBPα was significantly down-regulated and C/EBPβ was significantly up-regulated. C/EBPδ, on the other hand, was selectively down-regulated in the forebrain, a part of the brain showing high levels of fibrillar Aβ deposits. In contrast, no difference in expression levels of C/EBPδ between wild type and transgenic mice was detected in the relatively spared hindbrain. Finally, we show that interleukin-1β-induced C/EBPδ DNA binding activity to both C/EBP and κB sites is abolished after exposure to Aβ.</p> <p>Conclusions</p> <p>These data suggest that both expression and function of C/EBPδ are dysregulated in Alzheimer's disease. C/EBPδ seems to be differently regulated in response to different conformations of Aβ. We propose that Aβ induces an imbalance between NF-κB and C/EBP transcription factors that may result in abnormal responses to inflammatory stimuli.</p

Anchored FRET sensors detect local caspase activation prior to neuronal degeneration

<p>Abstract</p> <p>Background</p> <p>Recent studies indicate local caspase activation in dendrites or axons during development and in neurodegenerative disorders such as Alzheimer's disease (AD). Emerging evidences point to soluble oligomeric amyloid-β peptide as a causative agent in AD.</p> <p>Results</p> <p>Here we describe the design of fluorescence resonance energy transfer (FRET)-based caspase sensors, fused to the microtubule associated protein tau. Specific caspase sensors preferentially cleaved by caspase-3, -6 or -9 were expressed in differentiated human neuroblastoma SH-SY5Y cells. The anchoring of the sensors resulted in high FRET signals both in extended neurites and soma and made analysis of spatiotemporal signal propagation possible. Caspase activation was detected as loss of FRET after exposure to different stimuli. Interestingly, after staurosporine treatment caspase-6 activation was significantly delayed in neurites compared to cell bodies. In addition, we show that exposure to oligomer-enriched amyloid-β peptide resulted in loss of FRET in cells expressing sensors for caspase-3 and -6, but not -9, in both soma and neurites before neurite degeneration was observed.</p> <p>Conclusions</p> <p>Taken together, the results show that by using anchored FRET sensors it is possible to detect stimuli-dependent differential activation of caspases and to distinguish local from global caspase activation in live neuronal cells. Furthermore, in these cells oligomer-enriched amyloid-β peptide induces a global, rather than local activation of caspase-3 and -6, which subsequently leads to neuronal cell death.</p

Particulate mercury in the atmosphere: Its significance, transport, transformation and sources

The importance of particulate mercury (Hg(p)) in the transport, chemistry and deposition of this toxic metal has long been underestimated and largely ignored. While it was once believed to constitute a small percentage of total atmospheric mercury, Hg(p) may contribute a significant portion of the deposition of this metal to adjacent natural waters. Recent measurements of Hg(p) in several urban/industrial areas have documented that Hg can be associated with large particles (>2.5 μm) and in concentrations similar to those of the vapor phase Hg (ng/m 3 ). As part of ongoing effort to diagnose the sources, transport and deposition of Hg to the Great Lakes and other Great Waters, the University of Michigan Air Quality Laboratory (UMAQL) has investigated the physical and chemical properties of particulate-phase Hg in both urban and rural locations. It appears that particulate Hg may be the one of the most difficult of the Hg measurements to perform, and perhaps the one of the most important for deposition and source apportionment studies. Particulate Hg concentrations measured in rural areas of the Great Lakes Region and Vermont ranged from 1 to 86 pg/m 3 whereas Hg(p) levels in urban/industrialized areas were in the range 15 pg/m 3 to 1.2 ng/m 3 .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43909/1/11270_2005_Article_BF01189664.pd

Analysis of Nociceptive Information Encoded in the Temporal Discharge Patterns of Cutaneous C-Fibers

The generation of pain signals from primary afferent neurons is explained by a labeled-line code. However, this notion cannot apply in a simple way to cutaneous C-fibers, which carry signals from a variety of receptors that respond to various stimuli including agonist chemicals. To represent the discharge patterns of C-fibers according to different agonist chemicals, we have developed a quantitative approach using three consecutive spikes. By using this method, the generation of pain in response to chemical stimuli is shown to be dependent on the temporal aspect of the spike trains. Furthermore, under pathological conditions, gamma-aminobutyric acid resulted in pain behavior without change of spike number but with an altered discharge pattern. Our results suggest that information about the agonist chemicals may be encoded in specific temporal patterns of signals in C-fibers, and nociceptive sensation may be influenced by the extent of temporal summation originating from the temporal patterns.open0

Long-term Atmospheric Mercury Wet Deposition at Underhill, Vermont

Section 112(m) of the 1990 Clean Air Act Amendments, referred to as the Great Waters Program, mandated an assessment of atmospheric deposition of hazardous air pollutants (HAPs) to Lake Champlain. Mercury (Hg) was listed as a priority HAP and has continued to be a high priority for a number of national and international programs. An assessment of the magnitude and seasonal variation of atmospheric Hg levels and deposition in the Lake Champlain basin was initiated in December 1992 which included event precipitation collection, as well as collection of vapor and particle phase Hg in ambient air. Sampling was performed at the Proctor Maple Research Center in Underhill Center, VT. The range in the annual volume-weighted mean concentration for Hg in precipitation was 7.8–10.5 ng/l for the 11-year sampling period and the average amount of Hg deposited with each precipitation event was 0.10 μg/m 2 . The average amount of Hg deposited through precipitation each year from 1993 to 2003 was 9.7 μg/m 2 /yr. A seasonal pattern for Hg in precipitation is clearly evident, with increased Hg concentrations and deposition observed during spring and summer months. While a clear trend in the 11-year event deposition record at Underhill was not observed, a significant decrease in the event max-to-monthly ratio was observed suggesting that a major source influence was controlled over time. Discrete precipitation events were responsible for significant fractions of the monthly and annual loading of Hg to the forested ecosystem in Vermont. Monthly-averaged temperatures were found to be moderately correlated with monthly volume-weighted mean Hg concentrations ( r 2 =0.61) and Hg deposition ( r 2 =0.67) recorded at the Vermont site. Meteorological analysis indicated the highest levels of Hg in precipitation were associated with regional transport from the west, southwest, and south during the warmer months.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44444/1/10646_2004_Article_6260.pd

Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats

Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions

Mercury isotopes in a forested ecosystem: Implications for air‐surface exchange dynamics and the global mercury cycle

Forests mediate the biogeochemical cycling of mercury (Hg) between the atmosphere and terrestrial ecosystems; however, there remain many gaps in our understanding of these processes. Our objectives in this study were to characterize Hg isotopic composition within forests, and use natural abundance stable Hg isotopes to track sources and reveal mechanisms underlying the cycling of Hg. We quantified the stable Hg isotopic composition of foliage, forest floor, mineral soil, precipitation, and total gaseous mercury (THg (g) ) in the atmosphere and in evasion from soil, in 10‐year‐old aspen forests at the Rhinelander FACE experiment in northeastern Wisconsin, USA. The effect of increased atmospheric CO 2 and O 3 concentrations on Hg isotopic composition was small relative to differences among forest ecosystem components. Precipitation samples had δ 202 Hg values of −0.74 to 0.06‰ and ∆ 199 Hg values of 0.16 to 0.82‰. Atmospheric THg (g) had δ 202 Hg values of 0.48 to 0.93‰ and ∆ 199 Hg values of −0.21 to −0.15‰. Uptake of THg (g) by foliage resulted in a large (−2.89‰) shift in δ 202 Hg values; foliage displayed δ 202 Hg values of −2.53 to −1.89‰ and ∆ 199 Hg values of −0.37 to −0.23‰. Forest floor samples had δ 202 Hg values of −1.88 to −1.22‰ and ∆ 199 Hg values of −0.22 to −0.14‰. Mercury isotopes distinguished geogenic sources of Hg and atmospheric derived sources of Hg in soil, and showed that precipitation Hg only accounted for ~16% of atmospheric Hg inputs. The isotopic composition of Hg evasion from the forest floor was similar to atmospheric THg (g) ; however, there were systematic differences in δ 202 Hg values and MIF of even isotopes (∆ 200 Hg and ∆ 204 Hg). Mercury evasion from the forest floor may have arisen from air‐surface exchange of atmospheric THg (g) , but was not the emission of legacy Hg from soils, nor re‐emission of wet‐deposition. This implies that there was net atmospheric THg (g) deposition to the forest soils. Furthermore, MDF of Hg isotopes during foliar uptake and air‐surface exchange of atmospheric THg (g) resulted in the release of Hg with very positive δ 202 Hg values to the atmosphere, which is key information for modeling the isotopic balance of the global mercury cycle, and may indicate a shorter residence time than previously recognized for the atmospheric mercury pool. Key points Atmospheric Hg was fractionated during uptake by foliage (‐2.89 permil δ202Hg) Hg evading from soil was from atmospheric Hg interaction with soil environment Air‐surface exchange of Hg releases Hg with positive δ202Hg to global reservoirPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97463/1/2011GB004202RRts04.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97463/2/2011GB004202RRts05.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97463/3/2011GB004202RRts01.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97463/4/gbc20021.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97463/5/2011GB004202RRts06.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97463/6/2011GB004202RRts02.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97463/7/2011GB004202RRts07.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97463/8/2011GB004202RRts03.pd

Atmospheric sources, transport and deposition of mercury in Michigan: Two years of event precipitation

To assess the sources, transport and deposition of atmospheric mercury (Hg) in Michigan, a multi-site network was implemented in which Hg concentrations in event precipitation and ambient samples (vapor and participate phases) were determined. Results from the analysis of 2 years of event precipitation samples for Hg are reported here. The volume-weighted average Hg concentration in precipitation was 7.9, 10.8 and 10.2 ng/L for the Pellston, South Haven and Dexter sites, respectively. Yearly wet deposition of Hg for 1992–93 and 1993–94 was 5.8 and 5.5 μg/m 2 at Pellston, 9.5 and 12.7 μg/m 2 at South Haven and 8.7 and 9.1 μg/m at Dexter. A spatial gradient in both the Hg concentration and wet deposition was observed. Northern Michigan received almost half the deposition of Hg recorded at the southern Michigan sites. The concentration of Hg in precipitation exhibited a strong seasonal behavior with low values of 1.0 to 2.0 ng/L in winter and maximum values greater than 40 ng/L in summer. The spring, summer and autumn precipitation accounted for 89 to 91% of the total yearly Hg deposition. Mixed-layer back trajectories were calculated for each precipitation event to investigate the meteorological history and transport from potential Hg source regions. Elevated Hg concentrations were observed with air mass transport from the west, southwest, south, and southeast. At each of the sites precipitation events for which the Hg concentration was in the 90th and 10th percentile were-analyzed for trace elements by ICP-MS to investigate source impacts.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43912/1/11270_2005_Article_BF01189668.pd