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Selective 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 textSusceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis
No full textSporadische und familiäre AD haben möglicherweise einen gemeinsamen Mechanismus, der von der Aβ-Hypothese unabhängig ist. Neue Literaturrecherchen und mehr Veröffentlichungen zeigten unterschiedliche Mechanismen, die verdeutlichen, wie PS1 die neuronale Verschlechterung spezifisch bei FAD induziert. Wir haben Schritt für Schritt die Rolle von PS1 in einer γ-Sekretase-abhängigen und unabhängigen Weise bewiesen, die die normale zelluläre Wirkung auf Stress beeinflusst, unter Berücksichtigung der Einschränkungen eines zellulären Modells. Ein möglicher Mechanismus wurde im ER beschrieben, wo ER-Stress den UPR-Mechanismus aktivieren könnte. Obwohl wir in der Lage waren, ER-Stress zu induzieren, schien sich die zelluläre Reaktion darauf in der PS1-Mutante im Vergleich zu hPS1WT in N2a-Zellen nicht zu unterscheiden. Selbst eine durch Calcimycin induzierte Calciumveränderung reichte nicht aus, um Änderungen in der zellulären Reaktion auf ER-Stress zu induzieren. Autophagie war auch ein Schlüsselmechanismus, der seit vielen Jahren in AD verwandt ist. Unsere Ergebnisse korreliert Autophagie mit einer γ-Sekretase-unabhängigen Funktion von PS1, da wir nach Verwendung eines γ-Sekretase-Inhibitors (DAPT) nicht den gleichen Effekt sahen. Zuletzt hatten wir in unseren Experimenten PS1 und mitochondrialen Stress verbunden. Wir haben gezeigt, dass die mitochondriale Calciumdysregulation von PS1-Mutationen durch MPTP-Aktivierung abhängt und die mitochondriale und neuronale Toxizität im Kontext einer γ--Sekretase-abhängigen Funktion fördert. Zusammenfassend müssen weitere Studien zur zugrunde liegenden Veränderung der Zellorganellen und ihrer normalen Funktion durchgeführt werden, die sich nicht nur auf eine Aβ -Toxizität, sondern auch auf PS1-veränderte Funktionen beziehe
Distinct microglia profile in Creutzfeldt–Jakob disease and Alzheimer's disease is independent of disease kinetics
No full textEpidermal growth factor receptor overexpression is common and not correlated to gene copy number in ependymoma
No full textThe aim of this study was to investigate the epidermal growth factor receptor (EGFR) status in ependymoma specimens, as there is a need for new prognostic and druggable targets in this disease
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
Immune Activation in Amyloid-β-Related Angiitis Correlates with Decreased Parenchymal Amyloid-β Plaque Load
Get PDFBackground: Primary angiitis of the central nervous system (PACNS) is a rare but serious condition. A fraction of patients suffering from PACNS concurrently exhibit pronounced cerebral amyloid angiopathy (CAA) which is characterized by deposits of amyloid-β (Aβ) in and around the walls of small and medium-sized arteries of the brain. PACNS with CAA has been identified as a distinct disease entity, termed Aβ-related angiitis (ABRA). Evidence points to an immune reaction to vessel wall Aβ as the trigger of vasculitis. Objective: To investigate whether the inflammatory response to Aβ has (1) any effect on the status of immune activation in the brain parenchyma and (2) leads to clearance of Aβ from brain parenchyma. Methods: We studied immune activation and Aβ load by quantitative immunohistochemical analysis in brain parenchyma adjacent to affected vessels in 11 ABRA patients and 10 matched CAA controls. Results: ABRA patients showed significantly increased immune activation and decreased Aβ loads in the brain parenchyma adjacent to affected vessels. Conclusion: Our results are in line with the hypothesis of ABRA being the result of an excessive immune response to Aβ and show that this can lead to enhanced clearance of Aβ from the brain parenchyma by immune-mediated mechanisms
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
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