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gamma secretase

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A Anstey
No abstract text is available yet for this article.
March 2011: Journal of the Royal College of Physicians of Edinburgh
Masato Maesako, Kengo Uemura, Akira Kuzuya, Kazuki Sasaki, Megumi Asada, Kiwamu Watanabe, Koichi Ando, Masakazu Kubota, Takeshi Kihara, Ayae Kinoshita
Presenilin (PS), a causative molecule of familial Alzheimer disease, acts as a crucial component of the γ-secretase complex, which is required to cleave type I transmembrane proteins such as amyloid precursor protein and Notch. However, it also functions through γ-secretase-independent pathways. Recent reports suggested that PS could regulate the expression level of cell surface receptors, including the PDGF and EGF receptors, followed by modulating their downstream pathways via γ-secretase-independent mechanisms...
July 15, 2011: Journal of Biological Chemistry
Miguel Rodríguez-Manotas, Manuel Amorín-Díaz, Juan Cabezas-Herrera, Antonio Acedo-Martínez, Ismael Llorca-Escuín
Presenilins (PS1 and PS2) and the amyloid-β precursor protein (AβPP) are the only known proteins as causing monogenic Alzheimer's disease. AβPP is not the unique substrate of the γ-secretase complex. Presenilins are also implicated in the processing of Notch, an important developmental protein, which is thought to compete directly with AβPP for cleavage by γ-secretase. In the context of cleavages in alpha, beta and gamma and with the recent three-dimensional models of γ-secretase complex, a kinetic study of the sequential proteolysis of AβPP prompts us to think the possible existence of two entrance sites for substrate with only one exit site, a configuration depicting a lowercase gamma letter...
February 2012: Medical Hypotheses
Takayoshi Tokutake, Kensaku Kasuga, Ryuji Yajima, Yumi Sekine, Toshiyuki Tezuka, Masatoyo Nishizawa, Takeshi Ikeuchi
Alzheimer disease (AD) is neuropathologically characterized by the formation of senile plaques from amyloid-β (Aβ) and neurofibrillary tangles composed of phosphorylated Tau. Although there is growing evidence for the pathogenic role of soluble Aβ species in AD, the major question of how Aβ induces hyperphosphorylation of Tau remains unanswered. To address this question, we here developed a novel cell coculture system to assess the effect of extracellular Aβ at physiologically relevant levels naturally secreted from donor cells on the phosphorylation of Tau in recipient cells...
October 12, 2012: Journal of Biological Chemistry
Taisuke Tomita
No abstract text is available yet for this article.
November 2012: Nihon Rinsho. Japanese Journal of Clinical Medicine
Roma Olsauskas-Kuprys, Andrei Zlobin, Clodia Osipo
The numerous processes involved in the etiology of breast cancer such as cell survival, metabolism, proliferation, differentiation, and angiogenesis are currently being elucidated. However, underlying mechanisms that drive breast cancer progression and drug resistance are still poorly understood. As we discuss here in detail, the Notch signaling pathway is an important regulatory component of normal breast development, cell fate of normal breast stem cells, and proliferation and survival of breast cancer initiating cells...
2013: OncoTargets and Therapy
Shermali Gunawardena, Ge Yang, Lawrence S B Goldstein
Neurons and other cells require intracellular transport of essential components for viability and function. Previous work has shown that while net amyloid precursor protein (APP) transport is generally anterograde, individual vesicles containing APP move bi-directionally. This discrepancy highlights our poor understanding of the in vivo regulation of APP-vesicle transport. Here, we show that reduction of presenilin (PS) or suppression of gamma-secretase activity substantially increases anterograde and retrograde velocities for APP vesicles...
October 1, 2013: Human Molecular Genetics
Nikolaos K Robakis
Presenilins (PSs) are catalytic components of the γ-secretase complex that produces Aβ peptides. Substrates of γ-secretase are membrane-bound protein fragments deriving from the cleavage of extracellular sequence of cell surface proteins. APP-derived γ-secretase substrates are cleaved at gamma (γ) sites to produce Aβ while cleavage at the epsilon (ε) site produces AICD proposed to function in transcription. In addition to APP, γ-secretase promotes the ε-cleavage of a large number of cell surface proteins producing cytosolic peptides shown to function in cell signaling...
2014: Neurochemical Research
Ylenia Lombardo, Monica Faronato, Aleksandra Filipovic, Valentina Vircillo, Luca Magnani, R Charles Coombes
INTRODUCTION: Resistance to anti-estrogen therapies is a major cause of disease relapse and mortality in estrogen receptor alpha (ERα)-positive breast cancers. Tamoxifen or estrogen withdrawal increases the dependence of breast cancer cells on Notch signalling. Here, we investigated the contribution of Nicastrin and Notch signalling in endocrine-resistant breast cancer cells. METHODS: We used two models of endocrine therapies resistant (ETR) breast cancer: tamoxifen-resistant (TamR) and long-term estrogen-deprived (LTED) MCF7 cells...
June 11, 2014: Breast Cancer Research: BCR
Michalina Smolarkiewicz, Tomasz Skrzypczak, Michał Michalak, Krzysztof Leśniewicz, J Ross Walker, Gwyneth Ingram, Przemysław Wojtaszek
Gamma-secretase is a multisubunit complex with intramembrane proteolytic activity. In humans it was identified in genetic screens of patients suffering from familial forms of Alzheimer's disease, and since then it was shown to mediate cleavage of more than 80 substrates, including amyloid precursor protein or Notch receptor. Moreover, in animals, γ-secretase was shown to be involved in regulation of a wide range of cellular events, including cell signalling, regulation of endocytosis of membrane proteins, their trafficking, and degradation...
July 2014: Journal of Experimental Botany
Zsuzsanna Tucsek, Peter Toth, Danuta Sosnowska, Tripti Gautam, Matthew Mitschelen, Akos Koller, Gabor Szalai, William E Sonntag, Zoltan Ungvari, Anna Csiszar
There is growing evidence that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular damage and neuroinflammation, we compared young (7 months) and aged (24 months) high fat diet-fed obese C57BL/6 mice. Aging exacerbated obesity-induced systemic inflammation and blood-brain barrier disruption, as indicated by the increased circulating levels of proinflammatory cytokines and increased presence of extravasated immunoglobulin G in the hippocampus, respectively...
October 2014: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Andrea Giacomini, Fiorenza Stagni, Stefania Trazzi, Sandra Guidi, Marco Emili, Elizabeth Brigham, Elisabetta Ciani, Renata Bartesaghi
Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed...
October 2015: Neurobiology of Disease
Ping Li, Xi Lin, Jun-Rong Zhang, Yun Li, Jun Lu, Fei-Chao Huang, Chao-Hui Zheng, Jian-Wei Xie, Jia-Bin Wang, Chang-Ming Huang
Presenilin 1 (PS-1, encoded by PSEN1) is a part of the gamma- (γ-) secretase complex. Mutations in PSEN1 cause the majority of cases of familial Alzheimer's disease (FAD). Although in recent years PS-1 has been implicated as a tumor enhancer in various cancers, nothing is known regarding its role in gastric cancer (GC). In the present study, we investigate the role and clinical significance of PS-1 in GC. We observed that PS-1 was significantly upregulated and amplified in GC tissues and cell lines, and its aberrant expression was positively correlated with lymph node metastasis and with poor overall survival...
March 1, 2016: Oncotarget
Lorène Penazzi, Christian Tackenberg, Adnan Ghori, Nataliya Golovyashkina, Benedikt Niewidok, Karolin Selle, Carlo Ballatore, Amos B Smith, Lidia Bakota, Roland Brandt
Dendritic spines represent the major postsynaptic input of excitatory synapses. Loss of spines and changes in their morphology correlate with cognitive impairment in Alzheimer's disease (AD) and are thought to occur early during pathology. Therapeutic intervention at a preclinical stage of AD to modify spine changes might thus be warranted. To follow the development and to potentially interfere with spine changes over time, we established a long term ex vivo model from organotypic cultures of the hippocampus from APP transgenic and control mice...
June 2016: Neuropharmacology
Siladitta Biswas, Monica Adrian, Jochen Weber, Konstantin Evdokimov, Manuel Winkler, Cyrill Géraud
Leda-1/Pianp is a type I transmembrane protein expressed by CNS cells, murine melanoma cell line B16F10 and rat liver sinusoidal endothelial cells. The early steps of posttranslational modifications of Leda-1/Pianp have been described to include glycosylation and processing by proprotein convertases. Here, we comprehensively characterized the subsequent steps of proteolytic processing of Leda-1/Pianp. For this purpose specific protease inhibitors and cell lines deficient in PS1, PS2, PS1/PS2 and ADAM10/17 were deployed...
September 2, 2016: Biochemical and Biophysical Research Communications
A E Pink, D Dafou, N Desai, O Holmes, C Hobbs, C H Smith, P Mortimer, M A Simpson, R C Trembath, J N Barker
No abstract text is available yet for this article.
September 2016: British Journal of Dermatology
Frank Raven, Joseph F Ward, Katarzyna M Zoltowska, Yu Wan, Enjana Bylykbashi, Sean J Miller, Xunuo Shen, Se Hoon Choi, Kevin D Rynearson, Oksana Berezovska, Steven L Wagner, Rudolph E Tanzi, Can Zhang
A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations...
October 2017: EBioMedicine
Yan Yan, Ting-Hai Xu, Karsten Melcher, H Eric Xu
γ-Secretase is an intramembrane aspartyl protease that cleaves the C99 fragment of amyloid precursor protein to generate extracellular Aβ peptides. These peptides can oligomerize and aggregate to form amyloid plaques, processes that are widely believed to be causal for Alzheimer's disease. In spite of this critical function, it remains unknown how γ-secretase recognizes C99 and its other substrates, including Notch. In this study we determined E22-K55 as the minimal C99 fragment that was sufficient and required for initial cleavage...
October 2017: Acta Pharmacologica Sinica
Geraldine O'Sullivan Coyne, Therese S Woodring, Chyi-Chia R Lee, Alice P Chen, Heidi H Kong
No abstract text is available yet for this article.
April 2018: Journal of Investigative Dermatology
Hung-Jung Lin, Chien-Chin Hsu, Chung-Ching Chio, Yu-Feng Tian, Mao-Tsun Lin, Ting-Wei Lin, Chih-Hsien Chang, Ching-Ping Chang
BACKGROUND/AIMS: In response to traumatic brain injury (TBI), activated microglia exhibit changes in their morphology from the resting ramified phenotype toward the activated hypertrophic or amoeboid phenotype. Here, we provide the first description of the mechanism underlying the neuroprotective effects of γ-secretase inhibitors on TBI outcomes in rats. METHODS: The neuroprotective effects of γ-secretase inhibitors such as LY411575 or CHF5074 on TBI-induced neurotoxicity were analysed using a neurological motor function evaluation, cerebral contusion assay, immunohistochemical staining for microglia phenotypes, lung injury score and Evans Blue dye extravasation assay of brain and lung oedema...
2017: Cellular Physiology and Biochemistry
2017-12-13 13:54:32
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