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gamma secretase

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Courtney M Carroll, Yue-Ming Li
Gamma-secretase (GS) is an enzyme complex that cleaves numerous substrates, and it is best known for cleaving amyloid precursor protein (APP) to form amyloid-beta (Aβ) peptides. Aberrant cleavage of APP can lead to Alzheimer's disease, so much research has been done to better understand GS structure and function in hopes of developing therapeutics for Alzheimer's. Therefore, most of the attention in this field has been focused on developing modulators that reduce pathogenic forms of Aβ while leaving Notch and other GS substrates intact, but GS provides multiple avenues of modulation that could improve AD pathology...
April 28, 2016: Brain Research Bulletin
Eugene Futai
No abstract text is available yet for this article.
April 2016: Seikagaku. the Journal of Japanese Biochemical Society
Michael Willem, Sabina Tahirovic, Marc Aurel Busche, Saak V Ovsepian, Magda Chafai, Scherazad Kootar, Daniel Hornburg, Lewis D B Evans, Steven Moore, Anna Daria, Heike Hampel, Veronika Müller, Camilla Giudici, Brigitte Nuscher, Andrea Wenninger-Weinzierl, Elisabeth Kremmer, Michael T Heneka, Dietmar R Thal, Vilmantas Giedraitis, Lars Lannfelt, Ulrike Müller, Frederick J Livesey, Felix Meissner, Jochen Herms, Arthur Konnerth, Hélène Marie, Christian Haass
Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus...
October 15, 2015: Nature
Kunihiko Kanatsu, Taisuke Tomita
γ-Secretase is an intramembrane-cleaving protease that generates various forms of amyloid-β peptides (Aβ) that accumulate in the brains of Alzheimer's disease (AD) patients. The intracellular trafficking and subcellular localization of γ-secretase are linked to both qualitative and quantitative changes in Aβ production. However, the precise intracellular localization of γ-secretase as well as its detailed regulatory mechanisms have remained elusive. Recent genetic studies on AD provide ample evidence that alteration of the subcellular localization of γ-secretase contributes to the pathogenesis of AD...
September 1, 2016: Biological Chemistry
G Verdile, R N Martins, M Duthie, E Holmes, P H St George-Hyslop, P E Fraser
Presenilin 1 (PS1) plays a pivotal role in the production of the amyloid-beta protein, which is central to the pathogenesis of Alzheimer's disease. It has been demonstrated that PS1 regulates the gamma-secretase proteolysis of the amyloid precursor protein (APP) C-terminal fragment (APP-C100), which is the final step in amyloid-beta protein production. The mechanism and detailed pathway of this PS1 activity has yet to be fully resolved, but it may be due to a presenilin-controlled trafficking of the APP fragment or possibly an inherent PS1 proteolytic activity...
July 7, 2000: Journal of Biological Chemistry
Xiao-Juan Cheng, Yuan Gao, Yu-Wu Zhao, Xiao-Dong Cheng
Recent studies suggest that high-salt diet is associated with cognitive decline in human and mouse. The fact that genetic factors account for less than 50% cases of sporadic Alzheimer's disease (AD) highlights the important contribution of environmental factors, such as high-salt diet, in AD pathogenesis. However, whether and how high-salt diet fits the "amyloid cascade" hypothesis remains unexplored. Here, we show sodium chloride (NaCl) could increase Aβ levels in the medium of HEK293 cells overexpressing amyloid precursor protein (APP) or C99 fragment...
2015: PloS One
Andrés Ricardo López, Mitko Dimitrov, Hermeto Gerber, Virginie Braman, David L Hacker, Florian M Wurm, Patrick C Fraering
Alzheimer's disease (AD)-associated γ-secretase is a ubiquitously expressed multi-subunit protease complex embedded in the lipid bilayer of cellular compartments including endosomes and the plasma membrane. Although γ-secretase is of crucial interest for AD drug discovery, its atomic structure remains unresolved. γ-Secretase assembly and maturation is a multistep process, which includes extensive glycosylation on nicastrin (NCT), the only γ-secretase subunit having a large extracellular domain. These posttranslational modifications lead to protein heterogeneity that likely prevents the three-dimensional (3D) crystallization of the protease complex...
December 2015: Biotechnology and Bioengineering
Eun-Hye Jo, Ji-Seon Ahn, Jung-Soon Mo, Ji-Hye Yoon, Eun-Jung Ann, Hyeong-Jin Baek, Hye-Jin Lee, Seol-Hee Kim, Mi-Yeon Kim, Hee-Sae Park
The gamma-secretase is a multiprotein complex that cleaves many type-I membrane proteins, such as the Notch receptor and the amyloid precursor protein. Nicastrin (NCT) is an essential component of the multimeric gamma-secretase complex and functions as a receptor for gamma-secretase substrates. In this study, we found that Akt1 markedly regulated the protein stability of NCT. Importantly, the kinase activity of Akt1 was essential for the inhibition of gamma-secretase activity through degradation of NCT. Notably, the protein level of endogenous NCT was higher in shAkt1-expressing cells than in shCon-expressing cells...
September 2015: Journal of Neurochemistry
Ji-Yeun Hur, Hedvig Welander, Homira Behbahani, Mikio Aoki, Jenny Frånberg, Bengt Winblad, Susanne Frykman, Lars O Tjernberg
Several lines of evidence suggest that polymerization of the amyloid beta-peptide (Abeta) into amyloid plaques is a pathogenic event in Alzheimer's disease (AD). Abeta is produced from the amyloid precursor protein as the result of sequential proteolytic cleavages by beta-secretase and gamma-secretase, and it has been suggested that these enzymes could be targets for treatment of AD. gamma-Secretase is an aspartyl protease complex, containing at least four transmembrane proteins. Studies in cell lines have shown that gamma-secretase is partially localized to lipid rafts, which are detergent-resistant membrane microdomains enriched in cholesterol and sphingolipids...
March 2008: FEBS Journal
Yi Li, Christopher Bohm, Roger Dodd, Fusheng Chen, Seema Qamar, Gerold Schmitt-Ulms, Paul E Fraser, Peter H St George-Hyslop
The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane...
2014: Molecular Neurodegeneration
Jin Chu, Jian-Guo Li, Yash B Joshi, Phillip F Giannopoulos, Nicholas E Hoffman, Muniswamy Madesh, Domenico Praticò
BACKGROUND: A major feature of Alzheimer's disease (AD) is the accumulation of amyloid-beta (Aβ), whose formation is regulated by the gamma-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with gamma-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are unknown. METHODS: Postmortem brain tissue samples from AD patients, transgenic mouse models of AD, and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis...
April 15, 2015: Biological Psychiatry
Oxana Pester, Paul J Barrett, Daniel Hornburg, Philipp Hornburg, Rasmus Pröbstle, Simon Widmaier, Christoph Kutzner, Milena Dürrbaum, Aphrodite Kapurniotu, Charles R Sanders, Christina Scharnagl, Dieter Langosch
The etiology of Alzheimer's disease depends on the relative abundance of different amyloid-β (Aβ) peptide species. These peptides are produced by sequential proteolytic cleavage within the transmembrane helix of the 99 residue C-terminal fragment of the amyloid precursor protein (C99) by the intramembrane protease γ-secretase. Intramembrane proteolysis is thought to require local unfolding of the substrate helix, which has been proposed to be cleaved as a homodimer. Here, we investigated the backbone dynamics of the substrate helix...
January 30, 2013: Journal of the American Chemical Society
Mako Takami, Yu Nagashima, Yoshihisa Sano, Seiko Ishihara, Maho Morishima-Kawashima, Satoru Funamoto, Yasuo Ihara
Amyloid beta protein (Abeta), a pathogenic molecule associated with Alzheimer's disease, is produced by gamma-secretase, which cleaves the beta-carboxyl terminal fragment (betaCTF) of beta-amyloid precursor protein in the middle of its transmembrane domain. How the cleavage proceeds within the membrane has long been enigmatic. We hypothesized previously that betaCTF is cleaved first at the membrane-cytoplasm boundary, producing two long Abetas, Abeta(48) and Abeta(49), which are processed further by releasing three residues at each step to produce Abeta(42) and Abeta(40), respectively...
October 14, 2009: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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