1,720,966 research outputs found
MOLECULAR ASPECTS OF ALZHEIMER'S DISEASE PATHOGENESIS: FROM LOCAL SPINE TRAFFICKING TO LONG DISTANCE SPINE TO NUCLEUS SIGNALLING.'TOWARDS NEW THERAPEUTICS INTERVENTION'
No full textThe molecular pathogenesis of Alzheimer’s disease (AD) is still controversial, although genetic and cell biology findings indicate accumulation of Aβ, especially in soluble oligomeric conformation, as the driving force of synaptic dysfunction with concomitant activation of complex cascade of molecular events leading to dementia. In the last few years, several studies aimed at understanding how Aβ accumulation and assembly compromise synaptic structure and function of excitatory synapses. In this study, we evaluated how Aβ can affect the local and the long-distance trafficking, since the alteration of these mechanisms could represent a key determinant for synaptic dysfunction. We focused the attention on ADAM10, which activity prevents Aβ production. Notably the regulation of ADAM10 synaptic localization is neuronal activity-dependent, in particular LTP decrease, while LTD foster ADAM10 surface expression. Here we found that Aβ42 (500nM, 30 min) exposure results in an increase of ADAM10 synaptic availability. In particular, Aβ42 treatment leads to a decrease in the association between ADAM10 and AP2 complex, suggesting that the augment in ADAM10 synaptic localization is due to a decrease of the endocytosis. Interestingly, this mechanism is completely lost in the context of AD, suggesting that the increase in ADAM10 endocytosis, and thus the reduction of its activity towards APP, could be a synaptic mechanism of AD pathogenesis. In light of this consideration, we developed CPPs able to interfere with ADAM10 clathrin-mediated endocytosis and to restore the unbalance between exo- and endocytosis. This tool can be considered a potential disease-modifying strategy capable of modifying the progression of the disease and rescuing the pathological phenotype. Afterwards we describe a novel synapse-to-nucleus signaling pathway, involving the RNF10 protein, that specifically links activation of synaptic GluN2A-containing NMDARs to nuclear gene expression. In physiological conditions, RNF10 dissociates from the NMDAR complex in an activity-dependent manner and we provide compelling evidence for importin-dependent long-distance transport from synapto-dendritic compartments to the nucleus. These findings suggest that synaptonuclear trafficking of RNF10 is involved in the control of gene expression, which is necessary for synaptic plasticity in hippocampal neurons. Here we demonstrated that Aβ can affect RNF10 long-distance trafficking. In particular, during acute exposure, Aβ induces RNF10 translocation while in a chronic AD pathological context we found a reduction of the translocation, suggesting that RNF10 could be involved in AD pathogenesis
ADAM10 in Synaptic Physiology and Pathology
No full textGeneration of amyloid-β peptide is at the beginning of a cascade that leads to Alzheimer's disease. Amyloid precursor protein (APP) as well as β- and γ-secretases are the principal players involved in amyloid-β (Aβ) production, while α-secretase cleavage on APP prevents Aβ deposition. A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to act as α-secretase in neurons. Objective: Although localization of ADAM10 in the synaptic membrane is the key for its shedding activity, currently, very little is known about the mechanisms that control the synaptic abundance of ADAM10. Results: Two established forms of long-term activity-dependent plasticity, i.e. long-term potentiation and long-term depression (LTD), differentially regulate the synaptic availability and activity of ADAM10. Long-term potentiation decreases ADAM10 surface levels and activity by promoting its endocytosis. This process is mediated by activity-regulated association of ADAM10 with the clathrin adaptor protein 2 (AP2) complex. Conversely, LTD fosters ADAM10 insertion in the membrane and stimulates its activity. Furthermore, ADAM10 interaction with synapse-associated protein 97 (SAP97) is necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced spine morphology changes. Conclusions: Regulated interaction of ADAM10 with SAP97 and AP2 discloses a novel physiological mechanism of ADAM10 activity regulation at the synapses. This phenomenon produces a situation whereby synaptically regulated ADAM10 activity is positioned to modulate synaptic functionin
Trafficking in neurons: Searching for new targets for Alzheimer's disease future therapies
No full textAlzheimer's disease (AD) is the most common cause of dementia and no cure is available at the moment. As the disease progresses, patients become increasingly dependent, needing constant supervision and care. Prevention or delay of AD onset is among the most urgent moral, social, economic and scientific imperatives in industrialized countries. A better understanding of the pathogenic mechanisms leading to the disease and the consequent identification of new pharmacological targets are now a need. One of the most prominent molecular events occurring in AD patients' brains is the deposition of a peptide named amyloid-β (Aβ). Aβ derives from the concerted action of β-secretase, which mediates the amyloid precursor protein (APP) shedding at Aβ N-terminus, and γ-secretase, responsible for APP C-terminal stub cleavage. The production of Aβ can be prevented by the cleavage of ADAM10 on APP. In regard of AD pathogenesis, it is notable that neurons are the cell type affected in AD and that APP and the secretases are all integral transmembrane proteins, and so they are dynamically sorted in neurons. Therefore, neuronal sorting mechanisms responsible for APP and the secretases colocalization in the same membranous compartment play important roles in the regulation of Aβ production. In light of these considerations, this review provides an overview on the actual knowledge of the trafficking mechanisms involved in the regulation of APP and secretases localization, paying particular attention to the specific neuronal setting
Peptidi attivatori dell'enzima ADAM10 e relativi usi nel trattamento delle patologie caratterizzate da un aumento del peptide β-amiloide
No full textThe present intervention relates to new peptides that increase the activity of the enzyme ADAM10 by acting at various levels in the cascade of events that leads to the accumulation of the beta-amyloid peptide. Pharmaceutical compositions are also contemplated comprising activator peptides of the enzyme ADAM10 and the related uses in the medical field for the treatment and/or prevention of the pathologies wherein the increase or accumulation of the beta-amyloid peptide occurs, such as Alzheimer's Disease, head injury and post-traumatic stress disorder
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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