1,721,034 research outputs found
The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer's disease
Full text linkAlzheimer's disease (AD) is the most common form of progressive neurodegenerative disease characterized by cognitive impairment and mental disorders. The actual cause and cascade of events in the progression of this pathology is not fully determined. AD is multifaceted in nature and is linked to different multiple mechanisms in the brain. This aspect is related to the lack of efficacious therapies that could slow down or hinder the disease onset/progression. The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway. Recently, the endocannabinoid system emerged as a novel potential therapeutic target to treat AD. In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD, although the mechanisms that are involved are not fully elucidated. This review provides an update of this area. In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets
Effects of intrathecal administration of everolimus in a triple transgenic mouse model of Alzheimer's disease
No full textOverwhelming evidence shows a primary role for the mammalian target of rapamycin (mTOR) signaling in the pathogenesis of Alzheimer's disease (AD). To investigate the relation between Aβ and mTOR, we injected the synthetic analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent amyloid-β peptide (Aβ) and tau accumulation associated with cognitive decline. In particular, 6-month-old 3×Tg-AD mice and age-matched wild-type littermates (Non-Tg) were used. At this age, the 3×Tg-AD mice show early intraneuronal Aβ accumulation and tau mislocalization, which correlate with the onset of cognitive decline. The mTOR enzymatic activity and the levels of phosphorylated p70S6K, a downstream target of mTOR, was significantly increased in the 3×Tg-AD mice compared to control mice; centrally administered everolimus significantly reduced the phosphorylation of p70S6K and decreased the levels of APP and Aβ. The Aβ reduction was confirmed by immunohistochemical analysis. We next sought to investigate the effect of everolimus on the learning and memory of 3×Tg-AD mice, using three independent behavioral paradigms: the novel object recognition test, a behavioral task mainly dependent on multiple cortical areas, the inhibitory avoidance, which is highly dependent on the hippocampus and amygdala, and the spatial version of the Morris water maze, a hippocampal-dependent task. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits in the 3×Tg-AD mice. In conclusion, we show that autophagy induction via everolimus may represent a valid therapeutic strategy in AD when administered early in the disease progression
Everolimus rescues the early learning and memory deficits and ameliorates the AD-like pathology in the 3xTg-AD mice
No full textOverwhelming evidence shows a primary role for the mammalian target of rapamycin (mTOR) signaling in the pathogenesis of Alzheimer’s disease (AD). To investigate the relation between Aβ and mTOR, we injected the synthetic analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent amyloid-β peptide (Aβ) and tau accumulation associated with cognitive decline. In particular, 6-month-old 3×Tg-AD mice and age-matched wild-type littermates (Non-Tg) were used. At this age, the 3×Tg-AD mice show early intraneuronal Aβ accumulation and tau mislocalization, which correlate with the onset of cognitive decline. The mTOR enzymatic activity and the levels of phosphorylated p70S6K, a downstream target of mTOR, was significantly increased in the 3×Tg-AD mice compared to control mice; centrally administered everolimus significantly reduced the phosphorylation of p70S6K and decreased the levels of APP and Aβ. The Aβ reduction was confirmed by immunohistochemical analysis. We next sought to investigate the effect of everolimus on the learning and memory of 3×Tg-AD mice, using three independent behavioral paradigms: the novel object recognition test, a behavioral task mainly dependent on multiple cortical areas, the inhibitory avoidance, which is highly dependent on the hippocampus and amygdala, and the spatial version of the Morris water maze, a hippocampal-dependent task. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits in the 3×Tg-AD mice. In conclusion, we show that autophagy induction via everolimus may represent a valid therapeutic strategy in AD when administered early in the disease progression
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Depressive-like behavior is paired to monoaminergic alteration in a murine model of Alzheimer's disease
Full text linkBACKGROUND:
Neuropsychiatric signs are critical in primary caregiving of Alzheimer patients and have not yet been fully investigated in murine models.
METHODS:
18-month-old 3×Tg-AD male mice and their wild-type male littermates (non-Tg) were used. The open field test and the elevated plus maze test were used to evaluate anxiety-like behaviors, whereas the Porsolt forced swim test, the tail suspension test, and the sucrose preference test for antidepressant/depression-coping behaviors. Neurochemical study was conducted by microdialysis in freely-moving mice, analyzing the basal and K(+)-stimulated monoamine output in the frontal cortex and ventral hippocampus. Moreover by immunohistochemistry, we analysed the expression of Tyrosin hydroxylase and Tryptophan hydroxylase, which play a key role in the synthesis of monoamines.
RESULTS:
Aged 3×Tg-AD mice exhibited a higher duration of immobility in the forced swim and tail suspension tests (predictors of depression-like behavior) which was not attenuated by a noradrenaline reuptake inhibitor, desipramine. In the sucrose preference test, 3×Tg-AD mice showed a significantly lower sucrose preference compared to the non-Tg group, without any difference in total fluid intake. In contrast, the motor functions and anxiety-related emotional responses of 3×Tg-AD mice were normal, as detected by the open-field and elevated plus-maze tests. To strengthen these results, we then evaluated the monoaminergic neurotransmissions by in vivo microdialysis and immunohistochemistry. In particular, with the exception of the basal hippocampal dopamine levels, 3×Tg-AD mice exhibited a lower basal extracellular output of amines in the frontal cortex and ventral hippocampus and also a decreased extracellular response to K(+) stimulation. Such alterations occur with obvious local amyloid-β and tau pathologies and without gross alterations in the expression of Tyrosin and Tryptophan hydroxylase.
CONCLUSIONS:
These results suggest that 3×Tg-AD mice exhibit changes in depression-related behavior involving aminergic neurotrasmitters and provide an animal model for investigating AD with depression
Oleoylethanolamide: a new player in energy metabolism control. Role in food intake
No full textOleoylethanolamide (OEA) is a lipid amide produced by enterocytes upon the absorption of dietary fat and participates in the induction of satiety. Through indirect pathways, probably depending on the local activation of peroxisome-proliferator-activated receptor-alpha and involving afferent vagus nerve fibers, OEA signal is transmitted to the brain-stem and the hypothalamus, where it stimulates the release of oxytocin from magnocellular neurons. OEA mechanism might, thus, provide a novel target for the design of therapies controlling appetite. © 2011 Elsevier Ltd
The satiety signal oleoylethanolamide stimulates oxytocin neurosecretion from rat hypothalamic neurons
No full textThe anandamide monounsaturated analogue oleoylethanolamide (OEA) acts as satiety signal released from enterocytes upon the ingestion of dietary fats to prolong the interval to the next meal. This effect, which requires intact vagal fibers and intestinal PPAR-alpha receptors, is coupled to the increase of c-fos and oxytocin mRNA expression in neurons of the paraventricular nucleus (PVN) and is prevented by the intracerebroventricular administration of a selective oxytocin antagonist, thus suggesting a necessary role of oxytocinergic neurotransmission in the pro-satiety effect of OEA. By brain microdialysis and immunohistochemistry, in this study we demonstrate that OEA treatment can stimulate oxytocin neurosecretion from the PVN and enhance oxytocin expression at both axonal and somatodendritic levels of hypothalamic neurons. Such effects, which are maximum 2 h after OEA administration, support the hypothesis that the satiety-inducing action of OEA is mediated by the activation of oxytocin hypothalamic neurons. (C) 2013 Elsevier Inc. All rights reserved
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