Presenilins and the γ-secretase: still a complex problem

The presenilins form part of a complex of membrane proteins that are involved in the proteolytic cleavage of cell-surface molecules. This article reviews the history of the discovery of the presenilins, their role in the pathogenesis of Alzheimer's disease and in the metabolism of the amyloid-β precursor protein. Unanswered questions about their biochemical mechanism of action and their effects on Ca2+ homeostasis are examined

Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice

BACKGROUND Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS We examined whether heparin and enoxaparin influence APP processing and inhibit Aβ production in primary cortical cell cultures. Heparin and enoxaparin were incubated with primary cortical cells derived from Tg2576 mice, and the level of APP and proteolytic products of APP (sAPPα, C99, C83 and Aβ) was measured by western blotting. Treatment of the cells with heparin or enoxaparin had no significant effect on the level of total APP. However, both GAGs decreased the level of C99 and C83, and inhibited sAPPα and Aβ secretion. Heparin also decreased the level of β-secretase (BACE1) and α-secretase (ADAM10). In contrast, heparin had no effect on the level of ADAM17. CONCLUSIONS/SIGNIFICANCE The data indicate that heparin and enoxaparin decrease APP processing via both α- and β-secretase pathways. The possibility that GAGs may be beneficial for the treatment of AD needs further study.This work was funded by a project grant (490031) from the National Health and Medical Research Council of Australia (http://www.nhmrc.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

HLA gene expression is altered in whole blood and placenta from women who later developed preeclampsia

Preeclampsia is a multi-system disease that significantly contributes to maternal and fetal morbidity and mortality. In this study, we used a non-biased microarray approach to identify dysregulated genes in maternal whole blood samples which may be associated with the development of preeclampsia. Whole blood samples were obtained at 28 weeks of gestation from 5 women who later developed preeclampsia (cases) and 10 matched women with normotensive pregnancies (controls). Placenta samples were obtained from an independent cohort of 19 women with preeclampsia matched with 19 women with normotensive pregnancies. We studied gene expression profiles using Illumina microarray in blood and validated changes in gene expression in whole blood and placenta tissue by qPCR. We found a transcriptional profile differentiating cases from controls; 236 genes were significantly dysregulated in blood from women who developed preeclampsia. Functional annotation of microarray results indicated that most of the genes found to be dysregulated were involved in inflammatory pathways. Whilst general trends were preserved, only HLA-A was validated in whole blood samples from cases using qPCR (2.30 ± 0.9 fold change) whereas in placental tissue HLA-DRB1 expression was found to be significantly increased in samples from women with preeclampsia (5.88 ± 2.24 fold change). We have identified that HLA-A is up-regulated in the circulation of women who went on to develop preeclampsia. In placenta of women with preeclampsia we identified that HLA-DRB1 is up-regulated. Our data provide further evidence for involvement of the HLA gene family in the pathogenesis of preeclampsia

Subregional Hippocampal Thickness Abnormalities in Older Adults with a History of Heavy Cannabis Use.

Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age=66.6+7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CB- group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42)=9.96, p=0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42)=23.17, p<0.0001], and in the entire HC averaged over all subregions [F(1,42)=8.49, p=0.006]. Conclusions: Negative effects of chronic adolescent CB use on hippocampal structure are maintained well into late life. Because hippocampal cortical loss underlies and exacerbates age-related cognitive decline, these findings have profound implications for aging adults with a history of early life usage. Clinical Trial Registration: ClinicalTrials.gov # NCT01874886

Differential expression of microRNA-206 and its target genes in pre-eclampsia

Objectives: Pre-eclampsia is a multi-system disease that significantly contributes to maternal and fetal morbidity and mortality. In this study, we used a non-biased microarray approach to identify novel circulating miRNAs in maternal plasma that may be associated with pre-eclampsia. Methods: Plasma samples were obtained at 16 and 28 weeks of gestation from 18 women who later developed pre-eclampsia (cases) and 18 matched women with normotensive pregnancies (controls). We studied miRNA expression profiles in plasma and subsequently confirmed miRNA and target gene expression in placenta samples. Placental samples were obtained from an independent cohort of 19 women with pre-eclampsia matched with 19 women with normotensive pregnancies. Results: From the microarray, we identified 1 miRNA that was significantly differentially expressed between cases and controls at 16 weeks of gestation and 6 miRNAs that were significantly differentially expressed at 28 weeks. Following qPCR validation only one, miR-206, was found to be significantly increased in 28 week samples in women who later developed pre-eclampsia (1.4 fold change ± 0.2). The trend for increase in miR-206 expression was mirrored within placental tissue from women with pre-eclampsia. In parallel, IGF-1, a target gene of miR-206, was also found to be down-regulated (0.41 ± 0.04) in placental tissue from women with pre-eclampsia. miR-206 expression was also detectable in myometrium tissue and trophoblast cell lines. Conclusions: Our pilot study has identified miRNA-206 as a novel factor up-regulated in pre-eclampsia within the maternal circulation and in placental tissue

Excited States via Coupled Cluster Theory without Equation-of-Motion Methods: Seeking Higher Roots with Application to Doubly Excited States and Double Core Hole States

In this work, we revisited the idea of using the coupled-cluster ground state formalism to target excited states. Our main focus was targeting doubly excited states and double core hole states. Typical equation-of-motion (EOM) approaches for obtaining these states struggle without higher-order excitations than doubles. We showed that by using a non-aufbau determinant optimized via the maximum overlap method the CC ground state solver can target higher energy states. Furthermore, just with singles and doubles (i.e., CCSD), we demonstrated that the accuracy of $\Delta$CCSD and $\Delta$CCSD(T) far surpasses that of EOM-CCSD for doubly excited states. The accuracy of $\Delta$CCSD(T) is nearly exact for doubly excited states considered in this work. For double core hole states, we used an improved ansatz for greater numerical stability by freezing core hole orbitals. The improved methods, core valence separation (CVS)-$\Delta$CCSD and CVS-$\Delta$CCSD(T), were applied to the calculation of the double ionization potential of small molecules. Even without relativistic corrections, we observed qualitatively accurate results with CVS-$\Delta$CCSD and CVS-$\Delta$CCSD(T). Remaining challenges in $\Delta$CC include the description of open-shell singlet excited states with the single-reference CC ground state formalism as well as excited states with genuine multi-reference character. The tools and intuition developed in this work may serve as a stepping stone towards directly targeting arbitrary excited states using ground state CC methods

TRPM8 and Nav1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons

<p>Abstract</p> <p>Background</p> <p>Familial amyloidotic polyneuropathy (FAP) is a peripheral neuropathy caused by the extracellular accumulation and deposition of insoluble transthyretin (TTR) aggregates. However the molecular mechanism that underlies TTR toxicity in peripheral nerves is unclear. Previous studies have suggested that amyloidogenic proteins can aggregate into oligomers which disrupt intracellular calcium homeostasis by increasing the permeability of the plasma membrane to extracellular calcium. The aim of the present study was to examine the effect of TTR on calcium influx in dorsal root ganglion neurons.</p> <p>Results</p> <p>Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG) neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC), as well as by blockers of Na_v1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8) channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones.</p> <p>Conclusions</p> <p>These data suggest that activation of TRPM8 channels triggers the activation of Na_v1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.</p

GPS Estimates of Integrated Precipitable Water Aid Weather Forecasters

Global Positioning System (GPS) meteorology provides enhanced density, low-latency (30-min resolution), integrated precipitable water (IPW) estimates to NOAA NWS (National Oceanic and Atmospheric Adminis tration Nat ional Weather Service) Weather Forecast Offices (WFOs) to provide improved model and satellite data verification capability and more accurate forecasts of extreme weather such as flooding. An early activity of this project was to increase the number of stations contributing to the NOAA Earth System Research Laboratory (ESRL) GPS meteorology observing network in Southern California by about 27 stations. Following this, the Los Angeles/Oxnard and San Diego WFOs began using the enhanced GPS-based IPW measurements provided by ESRL in the 2012 and 2013 monsoon seasons. Forecasters found GPS IPW to be an effective tool in evaluating model performance, and in monitoring monsoon development between weather model runs for improved flood forecasting. GPS stations are multi-purpose, and routine processing for position solutions also yields estimates of tropospheric zenith delays, which can be converted into mm-accuracy PWV (precipitable water vapor) using in situ pressure and temperature measurements, the basis for GPS meteorology. NOAA ESRL has implemented this concept with a nationwide distribution of more than 300 "GPSMet" stations providing IPW estimates at sub-hourly resolution currently used in operational weather models in the U.S

Whole-Body Vibration Alleviates Symptoms of Morphine Withdrawal

Whole-body vibration at 80 Hz has previously been shown to blunt neuropathological markers and behavioral symptoms of alcohol dependence. Here, we evaluate its ability to ameliorate symptoms of morphine use and withdrawal. Behavioral and neurophysiological symptoms of withdrawal were reduced significantly by whole-body vibration treatment