Melanocortin receptor agonist NDP-α-MSH improves cognitive deficits and microgliosis but not amyloidosis in advanced stages of AD progression in 5XFAD and 3xTg mice

Introduction: Alzheimer's disease (AD) is the most frequent cause of dementia and still lacks effective therapy. Clinical signs of AD include low levels of endogenous melanocortins (MCs) and previous studies have shown that treatment with MC analogs induces neuroprotection in the early stages of AD.Methods: We investigated the neuroprotective role of MCs in two transgenic mouse models of severe AD using 5 and 7 month-old (mo) 5XFAD mice and 9 and 12 mo 3xTg mice. These mice were subjected to a chronic stimulation of MC receptors (MCRs) with MC analogue Nle4-D-Phe7-alpha-melanocyte stimulating hormone (NDP-alpha-MSH, 340 mu g/kg, i.p.). Mouse behavior and ex-vivo histological and biochemical analyses were performed after 50 days of treatment.Results:Our analysis demonstrated an improvement in cognitive abilities of AD mice at late stage of AD progression. We also showed that these protective effects are associated with decreased levels of hyperphosphorylated Tau but not with A beta burden, that was unaffected in the hippocampus and in the cortex of AD mice. In addition, an age-dependent NDP effect on glial reactivity was observed only in 3xTg mice whereas a global downregulation of p38 mitogen-activated protein kinase was selectively observed in 7 mo 5XFAD and 14 mo 3xTg mice.Conclusion: Our results suggest that MCR stimulation by NDP-alpha-MSH could represent a promising therapeutic strategy in managing cognitive decline also at late stage of AD, whereas the effects on neuroinflammation may be restricted to specific stages of AD progression

PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice

Background: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro. Then, we examined the impact of a genetic ablation of PCSK9 on cognitive performance in a severe mouse model of AD. Finally, in the same animals we evaluated the effect of PCSK9 loss on Aβ pathology, neuroinflammation, and brain lipids. Methods: For in vitro studies, U373 human astrocytoma cells were treated with Aβ fibrils and human recombinant PCSK9. mRNA expression of the proinflammatory cytokines and inflammasome-related genes were evaluated by q-PCR, while MCP-1 secretion was measured by ELISA. For in vivo studies, the cognitive performance of a newly generated mouse line - obtained by crossing 5XFADHet with PCSK9KO mice – was tested by the Morris water maze test. After sacrifice, immunohistochemical analyses were performed to evaluate Aβ plaque deposition, distribution and composition, BACE1 immunoreactivity, as well as microglia and astrocyte reactivity. Cholesterol and hydroxysterols levels in mouse brains were quantified by fluorometric and LC-MS/MS analyses, respectively. Statistical comparisons were performed according to one- or two-way ANOVA, two-way repeated measure ANOVA or Chi-square test. Results: In vitro, PCSK9 significantly increased IL6, IL1B and TNFΑ mRNA levels in Aβ fibrils-treated U373 cells, without influencing inflammasome gene expression, except for an increase in NLRC4 mRNA levels. In vivo, PCSK9 ablation in 5XFAD mice significantly improved the performance at the Morris water maze test; these changes were accompanied by a reduced corticohippocampal Aβ burden without affecting plaque spatial/regional distribution and composition or global BACE1 expression. Furthermore, PCSK9 loss in 5XFAD mice induced decreased microgliosis and astrocyte reactivity in several brain regions. Conversely, knocking out PCSK9 had minimal impact on brain cholesterol and hydroxysterol levels. Conclusions: In vitro studies showed a pro-inflammatory effect of PCSK9. Consistently, in vivo data indicated a protective role of PCSK9 ablation against cognitive impairments, associated with improved Aβ pathology and attenuated neuroinflammation in a severe mouse model of AD. PCSK9 may thus be considered a novel pharmacological target for the treatment of AD

Catalytic Transformations of Alkynes via Ruthenium Vinylidene and Allenylidene Intermediates

NOTICE: This is the peer reviewed version of the following book chapter: Varela J. A., González-Rodríguez C., Saá C. (2014). Catalytic Transformations of Alkynes via Ruthenium Vinylidene and Allenylidene Intermediates. In: Dixneuf P., Bruneau C. (eds) Ruthenium in Catalysis. Topics in Organometallic Chemistry, vol 48, pp. 237-287. Springer, Cham. [doi: 10.1007/3418_2014_81]. This article may be used for non-commercial purposes in accordance with Springer Verlag Terms and Conditions for self-archiving.Vinylidenes are high-energy tautomers of terminal alkynes and they can be stabilized by coordination with transition metals. The resulting metal-vinylidene species have interesting chemical properties that make their reactivity different to that of the free and metal π-coordinated alkynes: the carbon α to the metal is electrophilic whereas the β carbon is nucleophilic. Ruthenium is one of the most commonly used transition metals to stabilize vinylidenes and the resulting species can undergo a range of useful transformations. The most remarkable transformations are the regioselective anti-Markovnikov addition of different nucleophiles to catalytic ruthenium vinylidenes and the participation of the π system of catalytic ruthenium vinylidenes in pericyclic reactions. Ruthenium vinylidenes have also been employed as precatalysts in ring closing metathesis (RCM) or ring opening metathesis polymerization (ROMP). Allenylidenes could be considered as divalent radicals derived from allenes. In a similar way to vinylidenes, allenylidenes can be stabilized by coordination with transition metals and again ruthenium is one of the most widely used metals. Metalallenylidene complexes can be easily obtained from terminal propargylic alcohols by dehydration of the initially formed metal-hydroxyvinylidenes, in which the reactivity of these metal complexes is based on the electrophilic nature of Cα and Cγ, while Cβ is nucleophilic. Catalytic processes based on nucleophilic additions and pericyclic reactions involving the π system of ruthenium allenylidenes afford interesting new structures with high selectivity and atom economy

UniVibe: A novel user-friendly software for automated condition monitoring and diagnostics of geared transmission

Nowadays, huge emphasis is given to research on diagnostic tools in order to prevent and monitor the health status of gears and bearings. However, the link between advanced signal processing techniques and ease of use is still missing in commercial software tools. Actually, softwares that implement advanced signal processing techniques leak in ease user interaction and automated diagnostic procedures. Authors have developed a commercial software tool, called UniVibe, that attempts to fill the gap between high sensitivity in the diagnostics of faults in complex geared transmission and user-friendly interface. This work focuses on the description of the UniVibe core, highlighting its diagnostic capabilities on the basis of a real industrial case. Specifically, the automated procedure that shepherds the user to the successfully fault diagnosis of a complex geared transmission is pointed out

Psychopathology and dietary restriction: A comparison between eating disorders and Type 1 diabetes

The Authors studied psychological effects of chronic dietary restriction in different pathological groups, with exogenous or self prescribed dieting: a group of Type 1 diabetic subjects, and a group of chronic anorexic subjects. In addition to the comparison with a group of normal controls, the two groups with dietary restriction were compared to a group of bulimic subjects, who displayed dyscontrol of eating behaviour. Four groups of 11 young adult subjects (Anorexics, Bulimics, Type 1 Diabetics and Controls), age range 20-39 years, were studied by I.P.A.T. ASQ (anxiety questionnaire), I.P.A.T, CDQ (Clinical Depression Questionnaire) and Draw a Person test. Variance analysis showed significant differences between groups: both Eating disorders groups showed clinically relevant depression levels, that were significantly higher than controls, whereas Diabetic subjects had scores not different from normal controls. The variable dyscontrol over eating behaviour was related (Bulimic Ss.) to significantly higher level of anxiety in comparison with other groups. At Draw a Person test, Anorexic and Diabetic Ss. showed a less articulated body concept than normal and Bulimic Ss. While diabetes free from long term complications does not seem to be a cause of clinical depression or anxiety, the body dimension is involved in these subjects, in the area of cognitive and emotional dependence. Anxious and depressive components are instead an integrant part of Eating disorders psychopathology and of self-prescribed dietary restrictions

Psychopathology and dietary restriction: A comparison between eating disorders and Type 1 diabetes

The Authors studied psychological effects of chronic dietary restriction in different pathological groups, with exogenous or self prescribed dieting: a group of Type 1 diabetic subjects, and a group of chronic anorexic subjects. In addition to the comparison with a group of normal controls, the two groups with dietary restriction were compared to a group of bulimic subjects, who displayed dyscontrol of eating behaviour. Four groups of 11 young adult subjects (Anorexics, Bulimics, Type 1 Diabetics and Controls), age range 20-39 years, were studied by I.P.A.T. ASQ (anxiety questionnaire), I.P.A.T, CDQ (Clinical Depression Questionnaire) and Draw a Person test. Variance analysis showed significant differences between groups: both Eating disorders groups showed clinically relevant depression levels, that were significantly higher than controls, whereas Diabetic subjects had scores not different from normal controls. The variable dyscontrol over eating behaviour was related (Bulimic Ss.) to significantly higher level of anxiety in comparison with other groups. At Draw a Person test, Anorexic and Diabetic Ss. showed a less articulated body concept than normal and Bulimic Ss. While diabetes free from long term complications does not seem to be a cause of clinical depression or anxiety, the body dimension is involved in these subjects, in the area of cognitive and emotional dependence. Anxious and depressive components are instead an integrant part of Eating disorders psychopathology and of self-prescribed dietary restrictions

A regional and cellular analysis of the early intracellular and extracellular accumulation of Aβ in the brain of 5XFAD mice

Intracellular Aβ (iAβ) expression, extracellular Aβ (eAβ) plaque formation and microglial reactivity are characteristic neuropathological events of Alzheimer's disease (AD) and have been detected in several transgenic mouse models of this disease. In this work we decided to investigate the early (2–7 months of age) development of these phenomena at both regional and cellular levels in 5XFAD mice, a severe transgenic mouse model of AD. We demonstrated that 1) Aβ pathology develops in many but not all brain regions, 2) iAβ is transient and almost always followed by eAβ in grey matter regions, and the respective levels are roughly proportional, and 3) in about 1/3 of the grey matter regions with Aβ pathology and in several white matter regions, eAβ plaques can appear where no iAβ-positive structures were detected. We also showed that male and female mice share a similar regional and cellular pattern of Aβ pathology development that is more prominent in females. Early iAβ is associated to the activation of microglia, while subsequent formation of eAβ plaques is associated with markedly increased density of microglial cells that acquire a characteristic clustered phenotype. Present analysis is relevant to set a reference for pathophysiological studies and to define specific targets for the test of therapeutic interventions in this widely used AD transgenic model

Psychological factors in chronic pain patients waiting for motor cortex stimulation

Aim of this study was to evaluate if neurosurgical motor-cortex stimulation produce variations in personality traits, as assessed by Minnesota Multiphasic Personality Inventory 2 (MMPI-2), Clinical Depression Questionnaire (IPAT-CDQ) and Anxiety Scale Questionnaire (IPAT-ASQ) in functional chronic pain syndrome (CPS) subjects. Seven pharmacoresistent patients affected by CPS waiting for motor-cortex stimulation and a control group of six patients, admitted at the Neurosurgery Department, were considered in this study. Pre-Post assessment were performed for experimental group. Only pre-treatment assessments were performed in control group. Factorial and repeated measures Anovas were used for confrontations. In experimental group, compared to control group, Pre-treatment assessment showed high levels of Anxiety and pathological scores to Hs, D and Hy MMPI-2 scales. In the experimental group, Post-treatment showed a small decrease in the same scales. Notwithstanding the treatment seems produce slight variations on clinical scales, the personality pattern of chronic pain patients remains relatively stable

Neuromodulation of the perception of an illusion of length

The Müller-Lyer figure is a visual illusion in which two identical horizontal lines are perceived as different in their physical length because of the presence of fins (inducers) at the line ends. The Brentano illusion combines the two configurations of the Müller-Lyer illusion in one figure on the horizontal planum. In healthy subjects this configuration generates a displacement of the subjective midpoint of the horizontal line. In brain-damaged patients, with unilateral spatial neglect (USN+) without hemianopia (H-), the Brentano illusion is preserved, with illusory effects even enlarged in the contralesional hemispace. This finding suggests an inhibitory modulation of the top-down mechanisms on the bottom-up processing at the basis of such illusory phenomenon, likely mediated by the right posterior parietal cortex (PPC), which represents the main neural substrate of neglect. In order to verify the hypothesis that the attentional system can modulate the Brentano illusion and that this modulation is lateralized, a group of healthy subjects was tested with the Brentano Hemianopia Test (BHT) while receiving cathodal or sham transcranial Direct Current Stimulation (tDCS) to the right or left PPC. The results show an increase of the illusory effect after cathodal tDCS of the right PPC and a decrease after the stimulation of the left PPC. This evidence uphold the involvement of attention and its hemispheric asymmetry in modulating the perceptual processing underlying the Brentano illusion of length

Hostility direction in eating disorders: a wartegg test study

Assertiveness and direction of hostility have been studied in eating disorder patients with conflicting results: some studies did not show significant differences between anorexics and bulimics, while others found outward directed hostility in anorexic patients. Because of the interference of aggressiveness with therapeutic programs and of the influence of inward and outward hostility on psychopathological development, we studied hostility direction in anorexic and bulimic patients. We assessed 10 anorexic (age m:22; sd:6) and 10 bulimic (age m:28; sd:7) women by the wartegg projective method. Clinical groups were compared with a control group of 18 healthy subjects (age m:25; sd:6). ANOVA showed a significant difference between the control group and clinical groups on formal quality (p<0.05) of table V, and on affective quality (p<0.05), and formal quality (p<0.05) of table VI. Post Hoc analyses showed for table III (affective quality) a lower score of the bulimic group vs. the anorexic group (p<0.05) and the control group (p=0.07). For table V on formal quality, bulimic group had a lower score than the control group (p<0.01) and the bulimic group (p<0.05 and p=0.08). It seems that bulimic patients and few emotional and motivational resources, a lower level of future planning and a less adequate management of hostility control