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The cellular prion protein and its derived fragments in human prion diseases and their role as potential biomarkers
No full textSelective binding of high molecular mass assemblies of amyloid beta-peptide to prion protein in patients with Alzheimer's disease
No full textHigh molecular mass assemblies of amyloid-beta oligomers bind prion protein in patients with Alzheimer's disease
No full textAlzheimer's disease is the most common form of dementia and the generation of oligomeric species of amyloid-beta is causal to the initiation and progression of it. Amyloid-beta oligomers bind to the N-terminus of plasma membrane-beta ound cellular prion protein (PrPC) initiating a series of events leading to synaptic degeneration. Composition of bound amyloid-beta oligomers, binding regions within PrPC, binding affinities and modifiers of this interaction have been almost exclusively studied in cell culture or murine models of Alzheimer's disease and our knowledge on PrPC-amyloid-beta interaction in patients with Alzheimer's disease is limited regarding occurrence, binding regions in PrPC, and size of bound amyloid-beta oligomers. Here we employed a PrPC amyloid-beta binding assay and size exclusion chromatography on neuropathologically characterized Alzheimer's disease and non-demented control brains (n = 15, seven female, eight male, average age: 79.2 years for Alzheimer's disease and n = 10, three female, seven male, average age: 66.4 years for controls) to investigate amyloid-beta-PrPC interaction. PrPC-amyloid-beta binding always occurred in Alzheimer's disease brains and was never detected in non-demented controls. Neither expression level of PrPC nor known genetic modifiers of Alzheimer's disease, such as the PrPC codon 129 polymorphism, influenced this interaction. In Alzheimer's disease brains, binding of amyloid-beta to PrPC occurred via the PrPC N-terminus. For synthetic amyloid-beta(42), small oligomeric species showed prominent binding to PrPC, whereas in Alzheimer's disease brains larger protein assemblies containing amyloid-beta(42) bound efficiently to PrPC. These data confirm Alzheimer's disease specificity of binding of amyloid-beta to PrPC via its N-terminus in a large cohort of Alzheimer's disease/control brains. Differences in sizes of separated protein fractions between synthetic and brain-derived amyloid-beta binding to PrPC suggest that larger assemblies of amyloid-beta or additional non-amyloid-beta components may play a role in binding of amyloid-beta(42) to PrPC in Alzheimer's disease
Selective binding of high molecular mass assemblies of amyloid beta-peptide to prion protein in patients with Alzheimer's disease
No full textThe ADAM10-mediated shedding of the prion protein in humans and other mammals: characterization of cleavage site-specific antibodies
No full textSummary
Prion protein (PrPC) is a widely expressed GPI-anchored glycoprotein that naturally undergoes various proteolytic processes. Among these, PrP shedding, a cleavage mediated by the metalloprotease ADAM10, holds significant implications for neurodegenerative diseases. Recent studies suggest that the shed form of PrP (sPrP) acts as a signaling molecule in intercellular communication and plays crucial roles in PrP-related physiological functions. Despite being an evolutionarily conserved protein, the precise site of PrP cleavage and its responsible protease in humans, as well as the biological significance of this shedding process, have not been conclusively studied. In this study, by employing cleavage site prediction and producing/characterizing specific antibodies targeting human sPrP, we identified amino acid Y226 as the site of PrP shedding. Additionally, we demonstrated that the cleavage is solely mediated by ADAM10, similar to what has been previously reported in mice. Our experiments conducted within various models, including cell lines, neural stem cells, and brain organoids, reveal that stimulation of human PrP shedding can be achieved by certain PrP-binding molecules, such as antibodies, without directly affecting ADAM10, suggesting new avenues for therapeutic intervention. Furthermore, our cleavage site-specific antibodies targeting human sPrP can also detect respective shed forms of the protein in the brains of cattle, sheep, and deer (the most relevant animal species naturally affected by fatal and transmissible prion diseases), due to the similarities in the C-terminal amino acid sequences. In both prion and Alzheimer’s diseases, sPrP transitions from a physiological diffuse tissue distribution to a close association with misfolded protein aggregates, indicating a protective blocking activity towards harmful protein conformers and potential as a diagnostic marker. This study highlights the effectiveness of sPrP-specific antibodies for reliably and easily detecting this relevant fragment in human samples. Although the exact role of sPrP in neurodegenerative diseases remains largely undefined, its interaction with aggregates suggests it may have a significant functional role. These findings provide a crucial tool for further research and offer new avenues for exploring sPrP's potential impact on neurodegenerative and other disorders.Zusammenfassung
Das Prionprotein (PrP) ist ein weit verbreitetes GPI-verankertes Glykoprotein, das natürlicherweise verschiedenen proteolytischen Prozessen unterliegt. Unter diesen hat das PrP-Shedding, eine Spaltung, die durch die Metalloprotease ADAM10 vermittelt wird, bedeutende Auswirkungen auf neurodegenerative Erkrankungen. Aktuelle Studien legen nahe, dass die freigesetzte Form von PrP (sPrP) als Signalmolekül in der interzellulären Kommunikation fungiert und eine entscheidende Rolle bei physiologischen Funktionen im Zusammenhang mit PrP spielt. Obwohl es sich um ein evolutionär konserviertes Protein handelt, wurde die genaue Spaltstelle von PrP und die verantwortliche Protease beim Menschen sowie die biologische Bedeutung dieses Spaltungsprozesses noch nicht abschließend untersucht. In dieser Studie haben wir durch die Verwendung von Spaltstellenvorhersage und die Herstellung spezifischer Antikörper, die sich gegen humanes sPrP richten, die Aminosäure Y226 als die Spaltstelle von PrP identifiziert. Zusätzlich wurde bestätigt, dass die Spaltung exklusiv durch ADAM10 vermittelt wird, ähnlich wie zuvor bei Mäusen berichtet wurde. Unsere Experimente, die in verschiedenen Modellen einschließlich Zelllinien, neuralen Stammzellen und Hirnorganoiden durchgeführt wurden, zeigen, dass eine Stimulation des PrP-Sheddings beim Menschen durch bestimmte PrP-bindende Moleküle, wie z.B. Antikörper, möglich ist, ohne ADAM10 direkt zu beeinflussen, was neue Ansätze für therapeutische Interventionen nahelegt. Darüber hinaus können unsere neu generierten Antikörper, die gegen sPrP gerichtet sind, die entsprechenden freigesetzten Formen des Proteins auch in Gehirnen von Rindern, Schafen und Hirschen nachweisen (also den relevanten natürlicherweise von fatalen und übertragbaren Prionenerkrankungen betroffenen Tierarten), aufgrund der Ähnlichkeit der Spaltstellen. Sowohl bei Prionerkrankungen als auch der Alzheimer-Krankheit wechselt sPrP von einer physiologisch diffusen Verteilung im Hirngewebe zu einer engen Assoziation mit fehlgefalteten Proteinaggregaten, was auf eine möglicherweise schützende, blockierende Wirkung gegenüber toxischen Proteinkonformeren sowie sein Potenzial als diagnostischer Marker hinweist. Diese Studie hebt die Wirksamkeit von sPrP-spezifischen Antikörpern zur verlässlichen und einfachen Detektion dieses pathophysiologisch relevanten Fragments in menschlichen Proben hervor. Obwohl die genaue Rolle von sPrP bei neurodegenerativen Erkrankungen weitgehend ungeklärt bleibt, deutet seine Interaktion mit Aggregaten darauf hin, dass es eine signifikante funktionale Rolle spielen könnte. Diese Ergebnisse bieten ein wesentliches Werkzeug für die weiterführende Forschung auf dem Gebiet und eröffnen neue Wege zur Untersuchung des potenziellen Einflusses von sPrP auf neurodegenerative und auch andere Erkrankungen
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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