1,720,956 research outputs found
Genetic suppression of beta 2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies
No full textAccumulation of the microtubule-binding protein tau is a key event in several neurodegenerative disorders referred to as tauopathies, which include Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Thus, understanding the molecular pathways leading to tau accumulation will have a major impact across multiple neurodegenerative disorders. To elucidate the pathways involved in tau pathology, we removed the gene encoding the beta-2 adrenergic receptors (beta 2ARs) from a mouse model overexpressing mutant human tau. Notably, the number of beta 2ARs is increased in brains of AD patients and epidemiological studies show that the use of beta-blockers decreases the incidence of AD. The mechanisms underlying these observations, however, are not clear. We show that the tau transgenic mice lacking the beta 2AR gene had a reduced mortality rate compared with the parental tau transgenic mice. Removing the gene encoding the beta 2ARs from the tau transgenic mice also significantly improved motor deficits. Neuropathologically, the improvement in lifespan and motor function was associated with a reduction in brain tau immunoreactivity and phosphorylation. Mechanistically, we provide compelling evidence that the beta 2AR-mediated changes in tau were linked to a reduction in the activity of GSK3 beta and CDK5, two of the major tau kinases. These studies provide a mechanistic link between beta 2ARs and tau and suggest the molecular basis linking the use of beta-blockers to a reduced incidence of AD. Furthermore, these data suggest that a detailed pharmacological modulation of beta 2ARs could be exploited to develop better therapeutic strategies for AD and other tauopathies
Administration of a selective beta 2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease
No full textCurrently, there are no available approaches to cure or slow down the progression of Alzheimer's disease (AD), which is characterized by the accumulation of extracellular amyloid-beta (A beta) deposits and intraneuronal tangles that comprised hyperphosphorylated tau. The beta 2 adrenergic receptors (beta 2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to AD; however, these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent beta-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here, we show that administration of ICI 118,551 (ICI), a selective beta 2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI increased A beta levels and A beta plaque burden. Concomitantly, ICI-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic amyloid precursor protein processing. These results suggest that under the conditions used here, selective pharmacologic inhibition of beta 2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between beta 2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of beta blockers on AD. (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
beta(2) Adrenergic Receptor, Protein Kinase A (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models
No full textAlzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid beta peptide (A beta) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify beta(2)-adrenergic receptor (beta(2)AR) that mediates A beta-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3 alpha/beta, and Ca2+/calmodulin-dependent protein kinase II is increased significantly. Deletion of the beta(2)AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, A beta signals through a beta(2)AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. A beta also induces a beta(2)AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks A beta-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the beta(2)AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that beta(2)AR may represent a potential therapeutic target for preventing the development of AD
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
- …
