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https://www.readbyqxmd.com/read/28637867/full-length-cellular-beta-secretase-has-a-trimeric-subunit-stoichiometry-and-its-sulfur-rich-transmembrane-interaction-site-modulates-cytosolic-copper-compartmentalization
#1
Filip Liebsch, Mark R P Aurousseau, Tobias Bethge, Hugo McGuire, Silvia Scolari, Andreas Herrmann, Rikard Blunck, Derek Bowie, Gerd Multhaup
The beta-secretase (BACE1) initiates processing of the amyloid precursor protein (APP) into Aβ peptides, which have been implicated as central players in the pathology of Alzheimer disease. BACE1 has been described as a copper-binding protein and its oligomeric state as being monomeric, dimeric, and/or multimeric, but the native cellular stoichiometry has remained elusive. Here, by using single-molecule fluorescence and in vitro cross-linking experiments with photo-activatable unnatural amino acids, we show that full-length BACE1, independently of its subcellular localization, exists as trimers in human cells...
June 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28626832/fragment-binding-to-%C3%AE-secretase-1-without-catalytic-aspartate-interactions-identified-via-orthogonal-screening-approaches
#2
Frederik J R Rombouts, Richard Alexander, Erna Cleiren, Alex De Groot, Michel Carpentier, Joyce Dijkmans, Katleen Fierens, Stefan Masure, Diederik Moechars, Martina Palomino-Schätzlein, Antonio Pineda-Lucena, Andrés A Trabanco, Daan Van Glabbeek, Ann Vos, Gary Tresadern
An approach to identify β-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2...
February 28, 2017: ACS Omega
https://www.readbyqxmd.com/read/28626017/amyloid-beta-peptide-is-needed-for-cgmp-induced-long-term-potentiation-and-memory
#3
Agostino Palmeri, Roberta Ricciarelli, Walter Gulisano, Daniela Rivera, Claudia Rebosio, Elisa Calcagno, Maria Rosaria Tropea, Silvia Conti, Utpal Das, Subhojit Roy, Maria A Pronzato, Ottavio Arancio, Ernesto Fedele, Daniela Puzzo
High levels of amyloid-beta peptide (Aβ) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aβ are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aβ levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors (PDE5-Is) sildenafil and vardenafil induces a parallel release of Aβ due to a change in the approximation of amyloid precursor protein (APP) and the β-site APP cleaving enzyme 1 (BACE1)...
June 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28626014/bace1-cleavage-site-selection-critical-for-amyloidogenesis-and-alzheimer-s-pathogenesis
#4
Shuting Zhang, Zhe Wang, Fang Cai, Mingming Zhang, Yili Wu, Jing Zhang, Weihong Song
Mutations in amyloid β precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's Disease (AD) or protecting against dementia. Under normal conditions beta-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp(1) site to generate C99 for amyloid β protein (Aβ) production, and predominantly at major Glu(11) site to generate C89, resulting in truncated Aβ production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential β-cleavage site of BACE1 in APP from the Glu(11) site to the Asp(1) site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio...
June 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28624701/2-substituted-thio-n-4-substituted-thiazol-1h-imidazol-2-yl-acetamides-as-bace1-inhibitors-synthesis-biological-evaluation-and%C3%A2-docking-studies
#5
Gang Yan, Lina Hao, Yan Niu, Wenjie Huang, Wei Wang, Fengrong Xu, Lei Liang, Chao Wang, Hongwei Jin, Ping Xu
In this work, a series of 2-substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamide derivatives were developed as β-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. In addition, the selected compounds were tested with affinity (KD) towards BACE-1, blood brain barrier (BBB) permeability and cytotoxicity. The studies revealed that the most potent analog 41 (IC50 = 4.6 μM) with high predicted BBB permeability and low cellular cytotoxicity, could serve as a good lead structure for further optimization...
June 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28618005/bace1-inhibitor-lanabecestat-azd3293-in-a-phase-1-study-of-healthy-japanese-subjects-pharmacokinetics-and-effects-on-plasma-and-cerebrospinal-fluid-a%C3%AE-peptides
#6
Kei Sakamoto, Shunji Matsuki, Kyoko Matsuguma, Tatsuya Yoshihara, Naoki Uchida, Fumihiko Azuma, Muir Russell, Glen Hughes, Samantha Budd Haeberlein, Robert C Alexander, Susanna Eketjäll, Alan R Kugler
Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat...
June 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28617091/fragment-based-virtual-screening-approach-and-molecular-dynamics-simulation-studies-for-identification-of-bace1-inhibitor-leads
#7
Prabu Manoharan, Nanda Ghoshal
Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point...
June 15, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28611242/evaluation-of-%C3%AE-pet-outcome-measures-to-detect-disease-modification-induced-by-bace-inhibition-in-a-transgenic-mouse-model-of-alzheimer-s-disease
#8
Steven Deleye, Ann Marie Waldron, Jeroen Verhaeghe, Astrid Bottelbergs, Leonie Wyffels, Bianca Van Broeck, Xavier Langlois, Mark E Schmidt, Sigrid Stroobants, Steven Staelens
Purpose: In this study, we investigated the effects of chronic administration of an inhibitor of the β-site amyloid precursor protein -cleaving enzyme 1 (BACE1) on Alzheimer's- related pathology by multi-tracer positron emission tomography (PET) imaging in APPPS1-21 mice. Methods: Wild-type (WT) and APPPS1-21 (TG) mice received vehicle (VEH) or BACE inhibitor (60 mg/kg) initiated at 7 weeks of age. Outcome measures of brain metabolism, neuroinflammation and amyloid-β pathology were obtained through μPET imaging with (18)F-FDG, (18)F-PBR111 and (18)F-AV45 respectively...
June 13, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28608479/biosynthesis-of-novel-7-8-dihydroxyflavone-glycoside-derivatives-and-in-silico-study-of-their-effects-on-bace1-inhibition
#9
Ramesh Prasad Pandey, Prakash Parajuli, Anaya Raj Pokhrel, Jae Kyung Sohng
7,8-Dihydroxyflavone (7,8-DHF) has been conjugated with glucose moiety to produce glucoside derivatives. Three analogues of 7,8-DHF (7-O-β-D-glucosyl-8-hydroxyflavone, 7-hydroxy-8-O-β-D-glucosyl flavone, and 7,8-di-O-β-D-glucosylflavone) have been successfully produced from in vitro reaction using glycosyltransferase of Bacillus licheniformis. Production of these 7,8-DHF derivatives were shifted to cheaper and easier approach in this study by using engineered Escherichia coli BL21 (DE3) ΔpgiΔzwfΔushA cells in which the flow of glucose-6-phospahte toward glycolysis and pentose phosphate pathway and hydrolysis of UDP-α-D-glucose were blocked while directing the carbon flux toward UDP-α-D-glucose by over-expressing UDP-α-D-glucose pathway genes...
June 12, 2017: Biotechnology and Applied Biochemistry
https://www.readbyqxmd.com/read/28603494/yxqn-reduces-alzheimer-s-disease-like-pathology-and-cognitive-decline-in-appsweps1de9-transgenic-mice
#10
Xiaowan Wang, Runmin Song, Wenliang Lu, Ziyu Liu, Lichun Wang, Xiaojuan Zhu, Yanjun Liu, Zijie Sun, Jiang Li, Xiaomeng Li
Alzheimer's disease (AD) is the world's most common form of dementia, in which aggregation of amyloid-β (Aβ) is the hallmark. Unfortunately, few medicines have succeeded to completely cure AD. Yangxue Qingnao (YXQN) is a Chinese traditional medicine, and its pharmacological effect is improving cerebral blood flow. In this study, we firstly demonstrated that YXQN reduced AD-like pathology and cognitive impairment in APPswePS1dE9 (APP/PS1) mice with 2 months administration. Our data showed that YXQN substantially ameliorated behavioral defects in 10-month old APP/PS1 mice using Morris Water Maze and Y-maze tests, in which the cognitive ability of YXQN high-dose group approaches to wild type mice...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28600778/semisynthesis-and-biological-evaluation-of-prenylated-resveratrol-derivatives-as-multi-targeted-agents-for-alzheimer-s-disease
#11
Thanchanok Puksasook, Shinya Kimura, Sarin Tadtong, Jutamas Jiaranaikulwanitch, Jaturong Pratuangdejkul, Worawan Kitphati, Khanit Suwanborirux, Naoki Saito, Veena Nukoolkarn
A series of prenylated resveratrol derivatives were designed, semisynthesized and biologically evaluated for inhibition of β-secretase (BACE1) and amyloid-β (Aβ) aggregation as well as free radical scavenging and neuroprotective and neuritogenic activities, as potential novel multifunctional agents against Alzheimer's disease (AD). The results showed that compound 4b exhibited good anti-Aβ aggregation (IC50 = 4.78 µM) and antioxidant activity (IC50 = 41.22 µM) and moderate anti-BACE1 inhibitory activity (23...
June 9, 2017: Journal of Natural Medicines
https://www.readbyqxmd.com/read/28589443/metformin-a-future-therapy-for-neurodegenerative-diseases
#12
REVIEW
Magdalena Markowicz-Piasecka, Joanna Sikora, Aleksandra Szydłowska, Agata Skupień, Elżbieta Mikiciuk-Olasik, Kristiina M Huttunen
Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer's disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti-diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti-inflammatory properties...
June 6, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28589255/potential-anti-cholinesterase-and-%C3%AE-site-amyloid-precursor-protein-cleaving-enzyme-1-inhibitory-activities-of-cornuside-and-gallotannins-from-cornus-officinalis-fruits
#13
Himanshu Kumar Bhakta, Chan Hum Park, Takako Yokozawa, Takashi Tanaka, Hyun Ah Jung, Jae Sue Choi
Cholinesterase (ChE) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors are promising agents for the treatment of Alzheimer's disease (AD). In the present study, we examined the inhibitory activity of seven compounds isolated from the fruits of Cornus officinalis, cornuside, polymeric proanthocyanidins, 1,2,3-tri-O-galloyl-β-D-glucose, 1,2,3,6-tetra-O-galloyl-β-D-glucose, tellimagrandin I, tellimagrandin II, and isoterchebin, against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1...
June 6, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28585417/cyanobacterial-peptides-as-a-prototype-for-the-design-of-cathepsin-d-inhibitors
#14
Hao Xu, Keting Bao, Shuai Tang, Jing Ai, Haiyan Hu, Wei Zhang
Cathepsin D (Cath D) is overexpressed and secreted in a number of solid tumors and involved in the progress of tumor invasion, proliferation, metastasis, and apoptosis. Inhibition of Cath D is regarded as an attractive pathway for the development of novel anticancer drugs. Our previous studies revealed that tasiamide B, a cyanobacterial peptide that contained a statine-like unit, exhibited good inhibition against Cath D and other aspartic proteases. Using this natural product as prototype, we designed and synthesized three new analogs, which bear isophthalic acid fragment at the N-terminus and isobutyl amine (1), cyclopropyl amine (2), or 3-methoxybenzyl amine (3) moiety at the C-terminus...
June 6, 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/28576634/bace1-inhibitory-activity-and-molecular-docking-analysis-of-meroterpenoids-from-sargassum-serratifolium
#15
Su Hui Seong, Md Yousof Ali, Hyeung-Rak Kim, Hyun Ah Jung, Jae Sue Choi
A wide range of pharmacological properties of Sargassum spp. extracts and isolated components have been recognized. Although individual meroterpenoids of Sargassum species have been reported to possess strong activity against Alzheimer's disease (AD), the active compounds of Sargassum serratifolium have not been fully explored. Therefore, we evaluated the anti-AD activity of S. serratifolium extract through enzyme inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1)...
May 18, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28553224/docking-studies-and-biological-evaluation-of-a-potential-%C3%AE-secretase-inhibitor-of-3-hydroxyhericenone-f-from-hericium-erinaceus
#16
Chen Diling, Yong Tianqiao, Yang Jian, Zheng Chaoqun, Shuai Ou, Xie Yizhen
Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting approximately more than 5% of the population worldwide over the age 65, annually. The incidence of AD is expected to be higher in the next 10 years. AD patients experience poor prognosis and as a consequence new drugs and therapeutic strategies are required in order to improve the clinical responses and outcomes of AD. The purpose of the present study was to screen a certain number of potential compounds from herbal sources and investigate their corresponding mode of action...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28539221/lodopyridones-b-and-c-from-a-marine-sediment-derived-bacterium-saccharomonospora-sp
#17
Tu Cam Le, Chae-Yoon Yim, Songhee Park, Nikita Katila, Inho Yang, Myoung Chong Song, Yeo Joon Yoon, Dong-Young Choi, Hyukjae Choi, Sang-Jip Nam, William Fenical
HPLC-UV guided isolation of the culture broth of a marine bacterium Saccharomonospora sp. CNQ-490 has led to the isolation of two new natural products, lodopyridones B and C (1 and 2) along with the previously reported lodopyridone A (3). Their chemical structures were established from the interpretation of 2D NMR spectroscopic data and the comparison of NMR data with the lodopyridone A (3). Lodopyridones B and C (1 and 2) possess the thiazole, and chloroquinoline groups which are characteristic features of these molecules...
May 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28528948/multi-functional-activities-of-citrus-flavonoid-narirutin-in-alzheimer-s-disease-therapeutics-an-integrated-screening-approach-and-in-vitro-validation
#18
Sandipan Chakraborty, Soumalee Basu
Alzheimer's disease (AD) is a complex disorder and the disease mechanism is yet to be properly characterized. Over the years, "amyloid cascade" emerges as principal pathogenic event in AD. β-Secretase 1 (BACE1) controls the rate-limiting step in amyloid beta (Aβ) generation and Aβ rapidly aggregates to form neurotoxic amyloid fibrils. Oxidative stress is one of the principal mediators of the observed neurotoxicity of amyloid fibril. The disease pathogenesis involves induction of multiple signaling cascades and the cross-talk therein...
May 19, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28528185/simvastatin-ameliorate-memory-deficits-and-inflammation-in-clinical-and-mouse-model-of-alzheimer-s-disease-via-modulating-the-expression-of-mir-106b
#19
Wenzhong Huang, Zhenyu Li, Liandong Zhao, Wei Zhao
BACKGROUND: Alzheimer's disease (AD) as a neurodegenerative brain disorder is a devastating pathology leading to disastrous cognitive impairments and dementia, and several studies have shown that AD is closely related to the inflammation, so anti-inflammatory treatment may provide therapeutic benefits. In this study, the effect of simvastatin on inflammation was investigated and the underlying mechanisms were explored. METHODS: First, we tested the effect of simvastatin on AD in clinical research...
May 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28508374/autodock-and-autodocktools-for-protein-ligand-docking-beta-site-amyloid-precursor-protein-cleaving-enzyme-1-bace1-as-a-case-study
#20
Nehme El-Hachem, Benjamin Haibe-Kains, Athar Khalil, Firas H Kobeissy, Georges Nemer
Computational docking and scoring techniques have revolutionized structural bioinformatics by providing unprecedented insights on key aspects of ligand-receptor interaction. Docking is used for optimizing known drugs and for identifying novel binders by predicting their binding mode and affinity. AutoDock and AutoDockTools are free of charge techniques that have been extensively cited in the literature as essential tools in structure-based drug design. Moreover, these methods are fast enough to permit virtual screening of ligand libraries containing tens of thousands of compounds...
2017: Methods in Molecular Biology
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