1,720,958 research outputs found
Methylene blue reduces Aβ levels and rescues early cognitive deficit by increasing proteasome activity
No full textGlucocorticoids Exacerbate Cognitive Deficits in TDP-25 Transgenic Mice via a Glutathione-Mediated Mechanism: Implications for Aging, Stress and TDP-43 Proteinopathies
No full textThe accumulation of TDP-43 (transactive response DNA-binding protein 43) and its 25 kDa C-terminal fragment (TDP-25) is a hallmark of several neurodegenerative disorders, including frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). The majority of FTLD-TDP cases are due to loss of function mutations in the gene encoding progranulin, a secreted growth factor. In ALS, specific mutations in the gene encoding TDP-43 have been linked to the disease pathogenesis. In both cases, however, the penetrance of the mutations greatly increases during aging, suggesting that other genetic or environmental factors may facilitate the development of the disease. Using transgenic mice that overexpress the 25 kDa C-terminal fragment of TDP-43, here we show that glucocorticoids, stress hormones known to increase the brain susceptibility to neurotoxic insults, increase the levels of soluble TDP-25 and exacerbate cognitive deficits, without altering full-length TDP-43 levels. Additionally, we show that the mechanism underlying the glucocorticoid-mediated increase in TDP-25 levels is coupled to changes in the glutathione redox state. Glutathione is an antioxidant involved in protecting cells from damage caused by reactive oxygen species; notably, alterations in the ratio of reduced to oxidized glutathione, which is the primary determinant of the cellular redox state, are associated with aging and neurodegeneration. We show that restoring the ratio of reduced to oxidized glutathione blocks the glucocorticoid effects on TDP-25. These data show that glucocorticoids potentiate the neurotoxic action of TDP-25 by increasing its levels and clearly indicate the role of cellular oxidative damage in this process
Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice
No full textAccumulation of the transactive response DNA-binding protein 43 (TDP-43) is a major hallmark of several neurodegenerative disorders, collectively known as TDP-43 proteinopathies. The most common TDP-43 proteinopathies, frontotemporal lobar degeneration with TDP-43-positive inclusions, and amyotrophic lateral sclerosis, share overlapping neuropathological and clinical phenotypes. The development and detailed analysis of animal models of TDP-43 proteinopathies are critical for understanding the pathogenesis of these disorders. Transgenic mice overexpressing mutant human TDP-43 (herein referred to as hTDP-43) are characterized by neurodegeneration and reduced life span. However, little is known about the behavioral phenotype of these mice. Here we report the novel finding that hTDP-43 mice develop deficits in cognition, motor performance, and coordination. We show that these behavioral deficits are associated with the accumulation of nuclear and cytosolic TDP-43 C-terminal fragments, a decrease in endogenous TDP-43 levels, and synaptic loss. Our findings provide critical insights into disease pathology, and will help guide future preclinical studies aimed at testing the effects of potential therapeutic agents on the onset and progression of TDP-43 proteinopathies. (C) 2014 Elsevier Inc. All rights reserved
mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies
No full textAccumulation of tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies, which include Alzheimer's disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and aggregates to form neurofibrillary tangles. The molecular mechanisms leading to tau accumulation remain unclear and more needs to be done to elucidate them. Age is a major risk factor for all tauopathies, suggesting that molecular changes contributing to the aging process may facilitate tau accumulation and represent common mechanisms across different tauopathies. Here, we use multiple animal models and complementary genetic and pharmacological approaches to show that the mammalian target of rapamycin (mTOR) regulates tau phosphorylation and degradation. Specifically, we show that genetically increasing mTOR activity elevates endogenous mouse tau levels and phosphorylation. Complementary to it, we further demonstrate that pharmacologically reducing mTOR signaling with rapamycin ameliorates tau pathology and the associated behavioral deficits in a mouse model overexpressing mutant human tau. Mechanistically, we provide compelling evidence that the association between mTOR and tau is linked to GSK3 and autophagy function. In summary, we show that increasing mTOR signaling facilitates tau pathology, while reducing mTOR signaling ameliorates tau pathology. Given the overwhelming evidence that reducing mTOR signaling increases lifespan and healthspan, the data presented here have profound clinical implications for aging and tauopathies and provide the molecular basis for how aging may contribute to tau pathology. Additionally, these results provide preclinical data indicating that reducing mTOR signaling may be a valid therapeutic approach for tauopathies
Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease
No full textAmyloid beta (A beta) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of A beta similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in A beta levels in the individuals examined (2-20+ years). The NMR A beta peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR A beta was less prone to aggregation than human A beta. Nevertheless, both NMR and human A beta were equally toxic to mouse hippocampal neurons, suggesting that A beta neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of A beta with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression. (C) 2013 Elsevier Inc. All rights reserved
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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