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https://www.readbyqxmd.com/read/28203608/modeling-fragile-x-syndrome-in-neurogenesis-an-unexpected-phenotype-and-a-novel-tool-for-future-therapies
#1
Barbara Bardoni, Maria Capovilla, Enzo Lalli
FMRP is an RNA-binding protein involved in synaptic translation. Its absence causes a form of intellectual disability, the Fragile X syndrome (FXS). Small neuroanatomical abnormalities, present both in human and mouse FMRP-deficient brains, suggest a subtle critical role of this protein in neurogenesis. Stable depletion of FMRP has been obtained in a mouse embryonic stem cell line Fmr1 (shFmr1 ES) that does not display morphological alterations, but an abnormal expression of a subset of genes mainly involved in neuronal differentiation and maturation...
2017: Neurogenesis (Austin, Tex.)
https://www.readbyqxmd.com/read/28188785/sortilin-related-receptor-1-interacts-with-amyloid-precursor-protein-and-is-activated-by-6-shogaol-leading-to-inhibition-of-the-amyloidogenic-pathway
#2
Ji-Young Na, Kibbeum Song, Ju-Woon Lee, Sokho Kim, Jungkee Kwon
Sortilin-related receptor 1 (SORL1) is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate amyloid beta (Aβ). Although 6-shogaol, a constituent of ginger, has been reported to have anti-inflammatory and anti-oxidant effects on neuronal cells, research regarding the activation of SORL1 has not yet been reported. Here, we aimed to investigate whether 6-shogaol contributes to the increases in SORL1 that are related to Alzheimer's disease (AD). To clarify the effect of 6-shogaol as a possible activator of SORL1, we used SORL1 siRNA as a blockade of SORL1 in hippocampal neuronal cells (HT22)...
February 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28173812/anthocyanins-encapsulated-by-plga-peg-nanoparticles-potentially-improved-its-free-radical-scavenging-capabilities-via-p38-jnk-pathway-against-a%C3%AE-1-42-induced-oxidative-stress
#3
Faiz Ul Amin, Shahid Ali Shah, Haroon Badshah, Mehtab Khan, Myeong Ok Kim
BACKGROUND: In order to increase the bioavailability of hydrophilic unstable drugs like anthocyanins, we employed a polymer-based nanoparticles approach due to its unique properties such as high stability, improved bioavailability and high water-soluble drug loading efficiency. Anthocyanins constitute a subfamily of flavonoids that possess anti-oxidative, anti-inflammatory and neuroprotective properties. However, anthocyanins are unstable because their phenolic hydroxyl groups are easily oxidized into quinones, causing a reduced biological activity...
February 7, 2017: Journal of Nanobiotechnology
https://www.readbyqxmd.com/read/28157093/bace1-dynamics-upon-inhibition-with-a-bace-inhibitor-and-correlation-to-downstream-alzheimer-s-disease-markers-in-elderly-healthy-participants
#4
Maarten Timmers, Soraia Barão, Bianca Van Broeck, Ina Tesseur, John Slemmon, Katja De Waepenaert, Jennifer Bogert, Leslie M Shaw, Sebastiaan Engelborghs, Dieder Moechars, Marc Mercken, Luc Van Nueten, Luc Tritsmans, Bart de Strooper, Johannes Rolf Streffer
The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer's disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers...
February 1, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28115709/gleevec-shifts-app-processing-from-a-%C3%AE-cleavage-to-a-nonamyloidogenic-cleavage
#5
William J Netzer, Karima Bettayeb, Subhash C Sinha, Marc Flajolet, Paul Greengard, Victor Bustos
Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28103131/pediatric-palliative-care-needs-assessments-from-paper-forms-to-actionable-patient-care
#6
Meaghann Shaw Weaver, Denice Schroeder, Christopher Wichman, Sue Bace, Catherine Vail, Andrew Macfadyen
No abstract text is available yet for this article.
January 19, 2017: Journal of Palliative Medicine
https://www.readbyqxmd.com/read/28035928/consecutive-analysis-of-bace1-function-on-developing-and-developed-neuronal-cells
#7
Yuji Kamikubo, Nobumasa Takasugi, Kazue Niisato, Yoshie Hashimoto, Takashi Sakurai
The amyloid-β protein precursor (AβPP) is cleaved by a transmembrane protease termed β-site AβPP cleavage enzyme (BACE1), which is being explored as a target for therapy and prevention of Alzheimer's disease (AD). Although genetic deletion of BACE1 results in abolished amyloid pathology in AD model mice, it also results in neurodevelopmental phenotypes such as hypomyelination and synaptic loss, observed in schizophrenia and autism-like phenotype. These lines of evidence indicate that the inhibition of BACE1 causes adverse side effects during the neurodevelopmental stage...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28005987/metabolic-characterization-of-intact-cells-reveals-intracellular-amyloid-beta-but-not-its-precursor-protein-to-reduce-mitochondrial-respiration
#8
Patrick M Schaefer, Bjoern von Einem, Paul Walther, Enrico Calzia, Christine A F von Arnim
One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization...
2016: PloS One
https://www.readbyqxmd.com/read/27979361/-warming-up-with-endotrainer-prior-to-laparoscopic-cholecystectomy
#9
Alicia Troncoso-Bacelis, Jaime Soto-Amaro, Carlos Ramírez-Velázquez
BACKGROUND: Laparoscopic cholecystectomy is a safe and effective treatment and remains the gold standard in patients with benign disease. However it presents difficulties such as: the limited movement range of the instruments, the loss of depth perception, haptic feedback and the fulcrum effect. Previous training can optimize surgical performance in patients to master basic skills. OBJECTIVE: Assess the effectiveness of surgeons warming up with an endotrainer before performing laparoscopic cholecystectomy...
December 12, 2016: Cirugia y Cirujanos
https://www.readbyqxmd.com/read/27889467/treadmill-exercise-decreases-amyloid-%C3%AE-burden-possibly-via-activation-of-sirt-1-signaling-in-a-mouse-model-of-alzheimer-s-disease
#10
Jung-Hoon Koo, Eun-Bum Kang, Yoo-Sung Oh, Dae-Seung Yang, Joon-Yong Cho
Accumulation of amyloid-β (Aβ) correlates significantly with progressive cognitive deficits, a main symptom of Alzheimer's disease (AD). Although treadmill exercise reduces Aβ levels, the molecular mechanisms underlying the effects are not fully understood. We hypothesize that treadmill exercise decreases Aβ production and alleviates cognitive deficits by activating the non-amyloidogenic pathway via SIRT-1 signaling. Treadmill exercise improved cognitive deficits and alleviated neurotoxicity. Most importantly, treadmill exercise increased SIRT-1 level, which subsequently resulted in increased ADAM-10 level by down-regulation of ROCK-1 and upregulation of RARβ, ultimately facilitating the non-amyloidogenic pathway...
February 2017: Experimental Neurology
https://www.readbyqxmd.com/read/27853315/a%C3%AE-42-oligomers-modulate-%C3%AE-secretase-through-an-xbp-1s-dependent-pathway-involving-hrd1
#11
Yannis Gerakis, Julie Dunys, Charlotte Bauer, Fréderic Checler
The aspartyl protease β-site APP cleaving enzyme, BACE1, is the rate-limiting enzyme involved in the production of amyloid-β peptide, which accumulates in both sporadic and familial cases of Alzheimer's disease and is at the center of gravity of the amyloid cascade hypothesis. In this context, unravelling the molecular mechanisms controlling BACE1 expression and activity in both physiological and pathological conditions remains of major importance. We previously demonstrated that Aβ controlled BACE1 transcription in an NFκB-dependent manner...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27821233/-effect-and-mechanism-of-traditional-chinese-herbs-against-a%C3%AE-expression-in-brain-tissues-of-mice-with-alzheimer-s-disease
#12
N N Zhou, R Zhu, X M Zhao, P Liang
Objective: To investigate the effects of gastrodin, astragaloside and paeoniflorin from three types of traditional Chinese herbs against on β-amyloid plaques and memory ability in 5XFAD Alzheimer's disease (AD) transgenic mice. Methods: Seventy 5XFAD mice were randomly divided into seven groups, namely gastrodin-high and gastrodin-low dose groups (GAS-H, GAS-L), astragaloside-high and astragaloside-low dose groups (AST-H, AST-L), and paeoniflorin-high and paeoniflorin-low dose groups (PAE-H, PAE-L), and positive control group...
November 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/27807285/the-bace1-inhibitor-verubecestat-mk-8931-reduces-cns-%C3%AE-amyloid-in-animal-models-and-in-alzheimer-s-disease-patients
#13
Matthew E Kennedy, Andrew W Stamford, Xia Chen, Kathleen Cox, Jared N Cumming, Marissa F Dockendorf, Michael Egan, Larry Ereshefsky, Robert A Hodgson, Lynn A Hyde, Stanford Jhee, Huub J Kleijn, Reshma Kuvelkar, Wei Li, Britta A Mattson, Hong Mei, John Palcza, Jack D Scott, Michael Tanen, Matthew D Troyer, Jack L Tseng, Julie A Stone, Eric M Parker, Mark S Forman
β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys...
November 2, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27790089/proteomic-substrate-identification-for-membrane-proteases-in-the-brain
#14
REVIEW
Stephan A Müller, Simone D Scilabra, Stefan F Lichtenthaler
Cell-cell communication in the brain is controlled by multiple mechanisms, including proteolysis. Membrane-bound proteases generate signaling molecules from membrane-bound precursor proteins and control the length and function of cell surface membrane proteins. These proteases belong to different families, including members of the "a disintegrin and metalloprotease" (ADAM), the beta-site amyloid precursor protein cleaving enzymes (BACE), membrane-type matrix metalloproteases (MT-MMP) and rhomboids. Some of these proteases, in particular ADAM10 and BACE1 have been shown to be essential not only for the correct development of the mammalian brain, but also for myelination and maintaining neuronal connections in the adult nervous system...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27778760/effect-of-flavonoids-rich-extract-of-capparis-spinosa-on-inflammatory-involved-genes-in-amyloid-beta-peptide-injected-rat-model-of-alzheimer-s-disease
#15
Nazanin Mohebali, Seyed Abolhassan Shahzadeh Fazeli, Hossein Ghafoori, Zeinab Farahmand, Elham MohammadKhani, Faezeh Vakhshiteh, Abdolreza Ghamarian, Mansoureh Farhangniya, Mohammad Hossein Sanati
OBJECTIVES: Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Despite vast ongoing researches focusing on the area, little is known about novel treatments. In this study, we aimed to survey the effects of Capparis spinosa (C. spinosa) extract on amyloid-beta peptide (Aβ)-injected rat. METHODS: For this purpose, hydroalcoholic extracts of caper leaf and fruit were prepared. Total phenolic content, DPPH, and FRAP assay were accomplished to determine antioxidant activity of C...
October 25, 2016: Nutritional Neuroscience
https://www.readbyqxmd.com/read/27777836/affinity-capturing-and-surface-enrichment-of-a-membrane-protein-embedded-in-a-continuous-supported-lipid-bilayer
#16
Anders Gunnarsson, Lisa Simonsson Nyström, Sabina Burazerovic, Jenny Gunnarsson, Arjan Snijder, Stefan Geschwindner, Fredrik Höök
Investigations of ligand-binding kinetics to membrane proteins are hampered by their poor stability and low expression levels, which often translates into sensitivity-related limitations impaired by low signal-to-noise ratios. Inspired by affinity capturing of water-soluble proteins, which utilizes water as the mobile phase, we demonstrate affinity capturing and local enrichment of membrane proteins by using a fluid lipid bilayer as the mobile phase. Specific membrane-protein capturing and enrichment in a microfluidic channel was accomplished by immobilizing a synthesized trivalent nitrilotriacetic acid (tris-NTA)-biotin conjugate...
October 2016: ChemistryOpen
https://www.readbyqxmd.com/read/27770745/computational-insights-into-the-protonation-states-of-catalytic-dyad-in-bace1-acyl-guanidine-based-inhibitor-complex
#17
Abdulkadir Kocak, Ismail Erol, Muslum Yildiz, Hatice Can
Developing small compound based drugs targeting the β-secretase (BACE) enzyme is one of the most promising strategies in treatment of the Alzheimer's disease. As the enzyme shows the activity based on the acid-base reaction at a very narrow pH range, the protonation state of aspartic acids with the residue number 32 and 228 (Asp32 and Asp228), which forms the active site dyad, along with the protonation state of the ligand (substrate or inhibitor) play very critical role in interactions between the ligand and enzyme...
November 2016: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/27765347/neurohormetic-responses-of-quercetin-and-rutin-in-a-cell-line-over-expressing-the-amyloid-precursor-protein-appswe-cells
#18
Sagrario Martín-Aragón, Karim Lizeth Jiménez-Aliaga, Juana Benedí, Paloma Bermejo-Bescós
BACKGROUND: Plant secondary metabolites may induce adaptive cellular stress-responses in a variety of cells including neurons at the sub-toxic doses ingested by humans. Such 'neurohormesis' phenomenon, activated by flavonoids such as quercetin or rutin, may involve cell responses driven by modulation of signaling pathways which are responsible for its neuroprotective effects. PURPOSE: We attempt to explore the molecular mechanisms involved in the neurohormetic responses to quercetin and rutin exposure, in a SH-SY5Y cell line which stably overexpresses the amyloid precursor protein (APP) Swedish mutation, based on a biphasic concentration-response relationship for cell viability...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/27750032/prevention-of-tau-increase-in-cerebrospinal-fluid-of-app-transgenic-mice-suggests-downstream-effect-of-bace1-inhibition
#19
Juliane Schelle, Lisa Häsler, Jens C Göpfert, Thomas O Joos, Hugo Vanderstichele, Erik Stoops, Eva-Maria Mandelkow, Ulf Neumann, Derya R Shimshek, Matthias Staufenbiel, Mathias Jucker, Stephan A Kaeser
INTRODUCTION: The inhibition of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). We previously reported an age-related increase of tau protein in the cerebrospinal fluid (CSF) of amyloid-β (Aβ) precursor protein (APP) transgenic mice. METHODS: APP transgenic mice were treated with a potent BACE1 inhibitor. CSF tau and CSF Aβ levels were assessed. A novel high-sensitivity tau sandwich immunoassay was developed...
October 14, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/27730514/intranasal-insulin-administration-ameliorates-streptozotocin-icv-induced-insulin-receptor-dysfunction-neuroinflammation-amyloidogenesis-and-memory-impairment-in-rats
#20
N Rajasekar, Chandishwar Nath, Kashif Hanif, Rakesh Shukla
Alzheimer's disease (AD) is associated with reduced insulin level and impairment of insulin receptor (IR) signaling in the brain, which correlates to amyloid pathology, neuroinflammation, and synaptic neurotoxicity. Clinical studies show that intranasal insulin improves memory in AD patients without peripheral hypoglycemia. However, neuroprotective molecular mechanism of the beneficial effect of intranasal insulin in AD pathology is unexplored. Therefore, we investigated the role of intranasal insulin on intracerebroventricular (ICV) streptozotocin (STZ)-induced memory impairment in rats as evaluated in the Morris water maze test...
October 11, 2016: Molecular Neurobiology
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