Elisa Canepa

GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses.

BACKGROUND AND PURPOSE Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3‐cyclopentyloxy‐4‐methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR‐7b, on memory performance, nausea, hippocampal cAMP and amyloid‐β (Aβ) levels.

A new mass conservation approach to the study of CO2 advection in an alpine forest

A new method is proposed for the computation of CO2 Net Ecosystem Exchange (NEE) and its components in a forest ecosystem. Advective flux is estimated by taking into account the air mass conservation principle. For this purpose, wind and dry air density values on the surface of the control volume are first corrected and then the advective flux is estimated on the surface of the control volume. Turbulent flux is also computed along the surface of the control volume while storage flux is computed inside the volume. Additional characteristics of this method are that incompressibility of the mean flow is not assumed a priori, and that vertical and horizontal advective fluxes are not treated separately, but their sum is estimated directly. The methodology is applied to experimental data collected with a three-dimensional scheme at the alpine site of Renon during the Advex project (July 2005). The advection flux was found to be prevailing positive at night and negative during the day, as was found in previous studies on advection for the same site, but showed a lower scatter in half-hour calculated values. We tested the effect of its summation on turbulent and storage fluxes to produce half-hourly values of NEE. Nighttime NEE values were used in functional relations with soil temperature, daytime values with PPFD. The effect of addition of the advection component was an increase in the values of parameters indicating ecosystem respiration, quantum yield, and photosynthetic capacity. The coefficient of correlation between NEE and environmental drivers increased. (Less)

An overview about the study of downwash effects on dispersion of airborne pollutants

Abstract The aim of the present work is to give an overview about the state of the art of the study of the downwash phenomena of airborne pollutants. Accounting for the downwash of pollutant dispersion is of interest because it can contribute to the prevention of dangerous situations by determining in advance what configuration of buildings, stacks, and effluents could cause a high concentration of harmful effluents in a particular area. Recent and less recent studies concerning both building and stack downwash are presented. Some of the presented models are well established and implemented in regulatory air pollutions codes, while other ones are more sophisticated and still under development.

Cholesterol and Amyloid-β: Evidence for a Cross-Talk between Astrocytes and Neuronal Cells

Accumulating data supports the concept that alterations of cholesterol metabolism might influence the development of Alzheimers disease (AD), a neurodegenerative disorder characterized by progressive accumulation of amyloid-β (Aβ) peptides in the brain. Changes in the neuronal production of Aβ have been described as a function of cholesterol levels, thus suggesting a causal link between cholesterol homeostasis dysregulation and AD pathogenesis. Under physiological conditions, cholesterol uptake in the brain is efficiently prevented by the blood-brain barrier, and mature neurons are thought to rely on glial cells for their cholesterol supply. In the present study, we tested the hypothesis that Aβ may serve as a signaling molecule capable of informing the astroglial network about the neuronal need for cholesterol. Collectively, our data bolster this hypothesis and demonstrate, for the first time, that Aβ(42) exerts an inhibitory effect on the expression of the cholesterol transporter ABCA1 in cultured astrocytes. Accordingly, we also show that ABCA1 expression is reduced in the brain of AβPP/PS1 transgenic mice. These results provide a biological function for Aβ peptides and may help to define the pathogenic relationship between cholesterol metabolism in brain and AD.

Cholesterol and Alzheimer's disease: a still poorly understood correlation.

A large amount of evidence suggests a pathogenic link between cholesterol homeostasis dysregulation and Alzheimers disease (AD). In cell culture systems, the production of amyloid‐β (Aβ) is modulated by cholesterol, and studies on animal models have consistently demonstrated that hypercholesterolemia is associated with an increased deposition of cerebral Aβ peptides. Consequently, a number of epidemiological studies have examined the effects of cholesterol‐lowering drugs (i.e., statins) in the prevention and the treatment of AD. However, while retrospective studies suggested a potential benefit of statin therapy, clinical trials produced inconsistent results. Here, we summarize the main findings from in vitro and in vivo research where the correlation between cholesterol and the neurodegenerative disorder was investigated. Recognition of this correlation could be an important step forward for our understanding of AD pathogenesis and, possibly, for the development of new therapeutic strategies.

A novel mechanism for cyclic adenosine monophosphate-mediated memory formation: Role of amyloid beta.

Cyclic adenosine monophosphate (cAMP) regulates long‐term potentiation (LTP) and ameliorates memory in healthy and diseased brain. Increasing evidence shows that, under physiological conditions, low concentrations of amyloid β (Aβ) are necessary for LTP expression and memory formation. Here, we report that cAMP controls amyloid precursor protein (APP) translation and Aβ levels, and that the modulatory effects of cAMP on LTP occur through the stimulation of APP synthesis and Aβ production. Ann Neurol 2014;75:602–607

Cyclic adenosine monophosphate as an endogenous modulator of the amyloid‐β precursor protein metabolism

Besides playing a pathogenic role in Alzheimer disease, amyloid‐beta peptides are normally produced in low amounts in the brain, and several lines of evidence suggest that they can modulate synaptic plasticity and memory. As cyclic adenosine monophosphate (cAMP) is known to be involved in the same processes and the blockade of its degradation by phosphodiesterase 4 inhibitors has consistently shown beneficial effects on cognition, we investigated the possible correlation between this second messenger and Aβ peptides in neuronal N2a cells overexpressing the amyloid‐β precursor protein (APP). We herein report that the elevation of endogenous cAMP by rolipram increased APP protein expression and both its amyloidogenic and nonamyloidogenic processing. The effects of rolipram were reproduced by both the cAMP membrane‐permeant analog 8Br‐cAMP and the forskolin‐induced activation of adenylyl cyclase but were not affected by the PKA inhibitor H‐89. Our results demonstrate that, in neuronal cells, APP metabolism is physiologically modulated by cAMP and suggest that this might represent an additional mechanism through which the second messenger could influence memory functions.

safe_air Algorithms to simulate the transport of pollutant elements: a model validation exercise and sensitivity analysis

Abstract The safe_air model numerically simulates transport and diffusion of airborne pollutants at local and regional scales using Gaussian plume segments and/or puffs. This model is able to deal with both non-stationary and inhomogeneous conditions. safe_air Is composed of a meteorological pre-processor, the WINDS model, to build a three-dimensional (3D) wind field starting from available wind measurements, and by a pollutant dispersion simulator, the P6 model. This paper deals with two different algorithms included in P6, which allow the determination of the advection of plume elements using the 3D wind field reconstructed by WINDS. A validation exercise concerning the two cited algorithms has been performed using laboratory data from the Environmental Protection Agency wind tunnel RUSHIL experiments (flat terrain and a two-dimensional schematic hill, neutral atmospheric conditions). This paper also contains a sensitivity analysis concerning the same algorithms when the model is applied to a hypothetical emission above a very complex real orography (Regione Liguria, Italy).

Evaluation of the SAFE_AIR code against air pollution field and laboratory experiments.

Abstract The SAFE_AIR model simulates the transport and diffusion of airborne pollutants using Gaussian plume segments and/or puffs. The model is able to deal with both non-stationary and inhomogeneous conditions. SAFE_AIR is an evolution of the AVACTA II model “recommended” by the US Environmental Protection Agency. With respect to AVACTA II, SAFE_AIR contains a number of improvements among which: the complete change of the wind field generation, different algorithms calculating the wind field spatial average providing the advection velocities of pollutant elements, and a more realistic description of deposition patterns. The model evaluation of some aspects of SAFE_AIR was performed using field data (from the KNRC Katrex experiments, flat terrain, convectively unstable and neutral conditions) and laboratory data (from the EPA wind tunnel Rushil experiments, two-dimensional schematic hill, neutral conditions). This paper contains a comprehensive description of the results of these model evaluations. These exercises allowed us to draw some conclusions coherent with what one could expect from a similar model. Among them: (1) the model performance is better when the wind tunnel experiments are simulated than when an open-air experiment is performed; (2) the simulation results are in better agreement with measurements performed in an almost neutral atmosphere than with those performed in unstable conditions. (3) the model has still some problems in simulating emissions near the ground, while the results relative to elevated emissions are more satisfactory; (4) the choice of the σ -function is the most critical among the options considered in our numerical experiments. We believe these conclusions both rather general and useful as far as the calibration and operational use of SAFE_AIR are concerned.

Modulation of cAMP levels by high‐fat diet and curcumin and regulatory effects on CD36/FAT scavenger receptor/fatty acids transporter gene expression

Curcumin, a polyphenol from turmeric (Curcuma longa), reduces inflammation, atherosclerosis, and obesity in several animal studies. In Ldlr-/- mice fed a high-fat diet (HFD), curcumin reduces plasma lipid levels, therefore contributing to a lower accumulation of lipids and to reduced expression of fatty acid transport proteins (CD36/FAT, FABP4/aP2) in peritoneal macrophages. In this study, we analyzed the molecular mechanisms by which curcumin (500, 1000, 1500 mg/kg diet, for 4 months) may influence plasma and tissue lipid levels in Ldlr-/- mice fed an HFD. In liver, HFD significantly suppressed cAMP levels, and curcumin restored almost normal levels. Similar trends were observed in adipose tissues, but not in brain, skeletal muscle, spleen, and kidney. Treatment with curcumin increased phosphorylation of CREB in liver, what may play a role in regulatory effects of curcumin in lipid homeostasis. In cell lines, curcumin increased the level of cAMP, activated the transcription factor CREB and the human CD36 promoter via a sequence containing a consensus CREB response element. Regulatory effects of HFD and Cur on gene expression were observed in liver, less in skeletal muscle and not in brain. Since the cAMP/protein kinase A (PKA)/CREB pathway plays an important role in lipid homeostasis, energy expenditure, and thermogenesis by increasing lipolysis and fatty acid β-oxidation, an increase in cAMP levels induced by curcumin may contribute to its hypolipidemic and anti-atherosclerotic effects.