1,720,973 research outputs found
P44 transgenic mice have an early and dramatic increase in Aβ levels inthe brain: a possible role of IGF-1 signaling in the regulation of Aβproduction during aging.
No full textAging is the single most important risk factor for late-onset Alzheimer’s disease (LOAD), which represents 95 to 97% of all cases of AD. Our group has recently shown that normal aging of the brain is accompanied by a progressive activation of the second messenger ceramide, which is responsible for the molecular stabilization of BACE1 and consequent increase in β cleavage of the amyloid precursor protein (APP). Such event is triggered by an age-dependent up-regulation of p75NTR expression. Here, we have analyzed p75NTR/TrkA signaling, ceramide metabolism, APP processing, and Aβ generation in mice transgenic for p44, the short isoform of p53 (Genes and Development; 2004: 306). P44+/+ mice represent a model of early and accelerated aging associated with a marked over-activation of the insulin-like growth factor 1 (IGF-1) signaling pathway, an evolutionary conserved regulator of lifespan. P44+/+ mice brain revealed a dramatic increase in the expression levels of p75NTR, which was paralleled by decreased levels of TrkA. The expression levels of both p75NTR and TrkA observed in 1-month-old p44+/+ mice were similar to those observed in 30-month-old control animals. The marked increase in p75NTR expression was paralleled by similar changes in the levels of ceramide, BACE1, and β-APP-CTF. Finally, Aβ levels were found to be significantly higher in p44+/+ mice, when compared to age-matched control animals. Inhibition of ceramide production reduced the steady-state levels of both BACE1 and β-APP-CTF indicating a direct effect on the rate of β cleavage of APP. We conclude that the increased production of Aβ in p44+/+ mice is caused by the increased activation of the p75NTR-ceramide signaling pathway down-stream IGF-1 signaling
An aging pathway controls the TrkA to p75NTR receptor switch and amyloid beta-peptide generation.
No full textAging of the brain is characterized by marked changes in the expression levels of the neurotrophin receptors, TrkA and p75(NTR). An expression pattern in which TrkA predominates in younger animals switches to one in which p75(NTR) predominates in older animals. This TrkA-to-p75(NTR) switch is accompanied by activation of the second messenger ceramide, stabilization of beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1), and increased production of amyloid beta-peptide (Abeta). Here, we show that the insulin-like growth factor-1 receptor (IGF1-R), the common regulator of lifespan and age-related events in many different organisms, is responsible for the TrkA-to-p75(NTR) switch in both human neuroblastoma cell lines and primary neurons from mouse brain. The signaling pathway that controls the level of TrkA and p75(NTR) downstream of the IGF1-R requires IRS2, PIP3/Akt, and is under the control of PTEN and p44, the short isoform of p53. We also show that hyperactivation of IGF1-R signaling in p44 transgenic animals, which show an accelerated form of aging, is characterized by early TrkA-to-p75(NTR) switch and increased production of Abeta in the brai
IGF-R, the common regulator of life span, acts upstream of p75NTR in the regulation of Aβ generation during aging.
No full textOne of the main characteristics of Alzheimer’s disease is the abnormal accumulation of amyloid β-peptide (Aβ) in the form of senile (or amyloid) plaques. Even though aging is the single most important risk factor for Alzheimer’s disease (AD), the molecular events that connect normal aging to AD are unknown. We have recently shown that aging is characterized by a TrkA to p75NTR switch that activates the rate of Aβ generation through the second messenger ceramide. Here we have used neuroblastoma cell lines, primary neurons, and p44+/+ mice to identify the up-stream event that controls the TrkA to p75NTR transition. Our results indicate that the insulin-like growth factor receptor (IGF-R) controls the rate of Aβ generation by acting up-stream p75NTR/TrkA. Indeed, IGF-R signaling activates p75NTR expression while down-regulating TrkA; such effect is accompanied by activation of ceramide, increased expression of BACE1, and increased β cleavage of APP. Both antisense oligonucleotides and siRNA against IGF-R successfully blocked the activation of the p75NTR-ceramide signaling pathway with consequent reduction in β cleavage of APP. Similar results were obtained by over-expressing the phosphate and tensin homologue deleted on chromosome ten (PTEN), which blocks IGF-R signaling. In contrast, over-expression of p44, which releases the block of IGF-R signaling mediated by PTEN, was followed by up-regulation of p75NTR, down-regulation of TrkA, and consequent activation of BACE1-mediated cleavage of APP. Finally, pharmacologic inhibiton of IGF-R signaling, down-stream phosphatidyilinositol triphosphate (PIP3) successfully blocked the effects induced by IGF1. In conclusion, our results show that IGF-R, the common regulator of lifespan, controls the rate of Aβ generation during aging by switching neurotrophin signaling from TrkA to p75NTR, and consequent activation of the second messenger ceramide
An aging pathway controls the TrkA to p75NTR receptor switch and amyloid beta-peptide generation
No full textAging of the brain is characterized by marked changes in the expression levels of the neurotrophin receptors, TrkA and p75(NTR). An expression pattern in which TrkA predominates in younger animals switches to one in which p75(NTR) predominates in older animals. This TrkA-to-p75(NTR) switch is accompanied by activation of the second messenger ceramide, stabilization of beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1), and increased production of amyloid beta-peptide (Abeta). Here, we show that the insulin-like growth factor-1 receptor (IGF1-R), the common regulator of lifespan and age-related events in many different organisms, is responsible for the TrkA-to-p75(NTR) switch in both human neuroblastoma cell lines and primary neurons from mouse brain. The signaling pathway that controls the level of TrkA and p75(NTR) downstream of the IGF1-R requires IRS2, PIP3/Akt, and is under the control of PTEN and p44, the short isoform of p53. We also show that hyperactivation of IGF1-R signaling in p44 transgenic animals, which show an accelerated form of aging, is characterized by early TrkA-to-p75(NTR) switch and increased production of Abeta in the brai
Egr-1 and Hipk2 are required for the TrkA to p75(NTR) switch that occurs downstream of IGF1-R
No full textThe aging program mediated by IGF1-R is responsible for a naturally occurring TrkA to p75(NTR) switch that leads to activation of the second messenger ceramide and increased production of the Alzheimer's disease amyloid beta-peptide. Biochemical and genetic approaches that target IGF1-R signaling, p75(NTR), or ceramide are able to block the above events. Here, we show that the transcription factors Egr-1 and Hipk2 are required elements for the TrkA to p75(NTR) switch downstream of IGF1-R signaling. Specifically, Egr-1 is required for the upregulation of p75(NTR), whereas Hipk2 is required for the downregulation of TrkA. In fact, gene silencing of Egr-1 abolished the ability of IGF1 to upregulate p75(NTR), whereas similar approaches directed against Hipk2 blocked the downregulation of TrkA. In addition, IGF1 treatment favored binding of Egr-1 and Hipk2 to the promoter of p75(NTR) and TrkA, respectively. Finally, the expression levels of both Egr-1 and Hipk2 are upregulated in an age-dependent fashion. Such an event is opposed by caloric restriction, a model of delayed aging, and favored by the p44 transgene in p44(+/+) animals, a model of accelerated aging
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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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