1,720,982 research outputs found
Metabotropic glutamate receptors: the potential for therapeutic applications in Alzheimer's disease
No full textThe impact of metabotropic glutamate receptors into active neurodegenerative processes: A "dark side" in the development of new symptomatic treatments for neurologic and psychiatric disorders
No full textMetabotropic glutamate (mGlu) receptor ligands are under clinical development for the treatment of CNS disorders with high social and economic burden, such as schizophrenia, major depressive disorder (MDD), and Parkinson's disease (PD), and are promising drug candidates for the treatment of Alzheimer's disease (AD). So far, clinical studies have shown symptomatic effects of mGlu receptor ligands, but it is unknown whether these drugs act as disease modifiers or, at the opposite end, they accelerate disease progression by enhancing neurodegeneration. This is a fundamental issue in the treatment of PD and AD, and is also an emerging theme in the treatment of schizophrenia and MDD, in which neurodegeneration is also present and contribute to disease progression. Moving from in vitro data and preclinical studies, we discuss the potential impact of drugs targeting mGlu2, mGlu3, mGlu4 and mGlu5 receptor ligands on active neurodegeneration associated with AD, PD, schizophrenia, and MDD. We wish to highlight that our final comments on the best drug candidates are not influenced by commercial interests or by previous or ongoing collaborations with drug companies. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'
Designing trehalose-conjugated peptide inhibitors for the oligomerization and toxicity of Alzheimer’s Aβ 11th Naples
No full textAlzheimer Disease: A New Beginning or a Final Exit?
Full text linkToday, a new chapter is being written in the book of Alzheimer disease, one that is challenging the longstanding view that adult neurons are incapable of division, remain nonproliferative, and are terminally differentiated. Here, we review the provocative notion that, in Alzheimer disease, whole populations of nonstem cell neurons leave their quiescent state and re-enter into the cell cycle. However, such neuronal re-entry into the cell cycle is futile and ultimately leads to the neurodegeneration that typifies Alzheimer disease.Fil: Obrenovich, Mark E.. No especifíca;Fil: Raina, Arun K.. No especifíca;Fil: Ogawa, Osamu. No especifíca;Fil: Atwood, Craig S.. No especifíca;Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Smith, Mark A.. No especifíca
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
Molecular Connections between DNA Replication and Cell Death in β-Amyloid-Treated Neurons
No full textBackground: Ectopic cell cycle reactivation in neurons is associated with neuronal death in Alzheimer's disease. In cultured rodent neurons, synthetic β-amyloid (Aβ) reproduces the neuronal cell cycle re-entry observed in the Alzheimer's brain, and blockade of the cycle prevents Aβ-induced neurodegeneration. DNA polymerase-β, whose expression is induced by Aβ, is responsible for the DNA replication process that ultimately leads to neuronal death, but the molecular mechanism(s) linking DNA replication to neuronal apoptosis are presently unknown. Aim: To explore the role of a conserved checkpoint pathway started by DNA replication stress, namely the ATM-ATR/Claspin/Chk-1 pathway, in switching the neuronal response from DNA replication to apoptosis. Methods: Experiments were carried out in cultured rat cortical neurons challenged with toxic oligomers of Aβ protein. Results: Small inhibitory molecules of ATM/ATR kinase or Chk-1 amplified Aβ-induced neuronal DNA replication and apoptosis, as they were permissive to the DNA polymerase-β activity triggered by Aβ oligomers. Claspin, i.e., the adaptor protein between ATM/ATR kinase and the downstream Chk-1, was present on DNA replication forks of neurons early after Aβ challenge, and decreased at times coinciding with neuronal apoptosis. The caspase-3/7 inhibitor I maintained overtime the amount of Claspin loaded on DNA replication forks and, concomitantly, reduced neuronal apoptosis by holding neurons in the S phase. Moreover, a short phosphopeptide mimicking the Chk-1-binding motif of Claspin was able to prevent Aβ-challenged neurons from entering apoptosis. Conclusion: We speculate that, in the Alzheimer's brain, Claspin degradation by intervening factors may precipitate the death of neurons engaged into DNA replication
Targeting mGlu receptors for optimization of antipsychotic activity and disease-modifying effect in schizophrenia
No full textMetabotropic glutamate (mGlu) receptors are considered as candidate drug targets for the treatment of schizophrenia. These receptors form a family of eight subtypes (mGlu1 to −8), of which mGlu1 and −5 are coupled to Gq/11, and all other subtypes are coupled to Gi/o. Here, we discuss the possibility that selective ligands of individual mGlu receptor subtypes may be effective in controlling the core symptoms of schizophrenia, and, in some cases, may impact mechanisms underlying the progression of the disorder. Recent evidence indicates that activation of mGlu1 receptors inhibits dopamine release in the meso-striatal system. Hence, selective positive allosteric modulators (PAMs) of mGlu1 receptors hold promise for the treatment of positive symptoms of schizophrenia. mGlu5 receptors are widely expressed in the CNS and regulate the activity of cells that are involved in the pathophysiology of schizophrenia, such as cortical GABAergic interneurons and microglial cells. mGlu5 receptor PAMs are under development for the treatment of schizophrenia and cater the potential to act as disease modifiers by restraining neuroinflammation. mGlu2 receptors have attracted considerable interest because they negatively modulate 5-HT2A serotonin receptor signaling in the cerebral cortex. Both mGlu2 receptor PAMs and orthosteric mGlu2/3 receptor agonists display antipsychotic-like activity in animal models, and the latter drugs are inactive in mice lacking mGlu2 receptors. So far, mGlu3 receptors have been left apart as drug targets for schizophrenia. However, activation of mGlu3 receptors boosts mGlu5 receptor signaling, supports neuronal survival, and drives microglial cells toward an antiinflammatory phenotype. This strongly encourages research of mGlu3 receptors in schizophrenia. Finally, preclical studies suggest that mGlu4 receptors might be targeted by novel antipsychotic drugs, whereas studies of mGlu7 and mGlu8 receptors in animal models of psychosis are still at their infancy
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