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https://www.readbyqxmd.com/read/27910192/novel-tacrine-based-pyrano-3-4-5-6-pyrano-2-3-b-quinolinones-synthesis-and-cholinesterase-inhibitory-activity
#1
Roshanak Hariri, Zahra Afshar, Mohammad Mahdavi, Maliheh Safavi, Mina Saeedi, Zahra Najafi, Reyhaneh Sabourian, Elahe Karimpour-Razkenari, Najmeh Edraki, Farshad Homayouni Moghadam, Abbas Shafiee, Mahnaz Khanavi, Tahmineh Akbarzadeh
In order to develop effective anti-cholinesterase compounds, a novel series of pyrano[3',4':5,6]pyrano[2,3-b]quinolinones were designed, synthesized, and evaluated in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All derivatives showed very good AChE inhibitory (AChEI) activity (IC50  = 0.37-5.62 μM) compared with rivastigmine (IC50  = 11.07 μM). Among them, 11-amino-12-(2,3-dichlorophenyl)-3-methyl-7,8,9,10-tetrahydropyrano[3',4':5,6]pyrano[2,3-b]quinolin-1(12H)-one (6f) displayed the best inhibitory activity...
December 2016: Archiv der Pharmazie
https://www.readbyqxmd.com/read/27902765/loss-of-cathepsin-b-and-l-leads-to-lysosomal-dysfunction-npc-like-cholesterol-sequestration-and-accumulation-of-the-key-alzheimer-s-proteins
#2
Stjepko Cermak, Marko Kosicek, Aleksandra Mladenovic-Djordjevic, Kosara Smiljanic, Selma Kanazir, Silva Hecimovic
Proper function of lysosomes is particularly important in neurons, as they cannot dilute accumulated toxic molecules and aggregates by cell division. Thus, impairment of lysosomal function plays an important role in neuronal degeneration and in the pathogenesis of numerous neurodegenerative diseases. In this work we analyzed how inhibition and/or loss of the major lysosomal proteases, the cysteine cathepsins B and L (CtsB/L), affects lysosomal function, cholesterol metabolism and degradation of the key Alzheimer's disease (AD) proteins...
2016: PloS One
https://www.readbyqxmd.com/read/27895104/bin1-and-cd2ap-polarise-the-endocytic-generation-of-beta-amyloid
#3
Florent Ubelmann, Tatiana Burrinha, Laura Salavessa, Ricardo Gomes, Cláudio Ferreira, Nuno Moreno, Cláudia Guimas Almeida
The mechanisms driving pathological beta-amyloid (Aβ) generation in late-onset Alzheimer's disease (AD) are unclear. Two late-onset AD risk factors, Bin1 and CD2AP, are regulators of endocytic trafficking, but it is unclear how their endocytic function regulates Aβ generation in neurons. We identify a novel neuron-specific polarisation of Aβ generation controlled by Bin1 and CD2AP We discover that Bin1 and CD2AP control Aβ generation in axonal and dendritic early endosomes, respectively. Both Bin1 loss of function and CD2AP loss of function raise Aβ generation by increasing APP and BACE1 convergence in early endosomes, however via distinct sorting events...
November 28, 2016: EMBO Reports
https://www.readbyqxmd.com/read/27891075/bace1-rnai-restores-the-composition-of-phosphatidylethanolamine-derivates-related-to-memory-improvement-in-aged-3xtg-ad-mice
#4
Javier G Villamil-Ortiz, Alvaro Barrera-Ocampo, Diego Piedrahita, Claudia M Velásquez-Rodríguez, Julian D Arias-Londoño, Gloria P Cardona-Gómez
β-amyloid (Aβ) is produced by the β-secretase 1 (BACE1)-mediated enzymatic cleavage of the amyloid precursor protein through the amyloidogenic pathway, making BACE1 a therapeutic target against Alzheimer's disease (AD). Alterations in lipid metabolism are a risk factor for AD by an unknown mechanism. The objective of this study was to determine the effect of RNA interference against BACE1 (shBACEmiR) on the phospholipid profile in hippocampal CA1 area in aged 3xTg-AD mice after 6 and 12 months of treatment compared to aged PS1KI mice...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27889855/epigallocatechin-gallate-attenuates-%C3%AE-amyloid-generation-and-oxidative-stress-involvement-of-ppar%C3%AE-in-n2a-app695-cells
#5
Zhao-Xu Zhang, Yan-Bing Li, Rui-Ping Zhao
The accumulation of β-amyloid (Aβ) peptide plaques is a major pathogenic event in Alzheimer's disease (AD). Aβ is a cleaved fragment of APP via BACE1, which is the rate-limiting enzyme in APP processing and Aβ generation. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered to be a potential target for AD treatment, because of its potent antioxidant and inhibitory effects on Aβ production by negatively regulating BACE1. Epigallocatechin gallate (EGCG), a highly active catechin found in green tea, is known to enhance metabolic activity and cognitive ability in the mice model of AD...
November 26, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27889245/selagintriflavonoids-with-bace1-inhibitory-activity-from-the-fern-selaginella-doederleinii
#6
Zhenxing Zou, Pingsheng Xu, Guogang Zhang, Fei Cheng, Kai Chen, Jing Li, Weixing Zhu, Dongsheng Cao, Kangping Xu, Guishan Tan
Eight triflavonoids, selagintriflavonoids A-H, were isolated from whole herbs of Selaginella doederleinii. The structures of compounds selagintriflavonoids A-C consisted of three naringenin units, whereas those of selagintriflavonoids D-H consisted of apigenin and two naringenin moieties. The structures and absolute configurations of the compounds were determined based on NMR, HRESIMS, and experimental and calculated electronic circular dichroism (ECD) data. The ability of the compounds to inhibit β-secretase (BACE1) was also evaluated...
November 23, 2016: Phytochemistry
https://www.readbyqxmd.com/read/27883916/hydrogen-sulfide-ameliorates-learning-memory-impairment-in-app-ps1-transgenic-mice-a-novel-mechanism-mediated-by-the-activation-of-nrf2
#7
Yuangui Liu, Yuanyuan Deng, Huiyu Liu, Caixia Yin, Xiaohui Li, Qihai Gong
Beta-amyloid (Aβ) plaques and oxidative stress are associated with the pathogenesis of Alzheimer's disease (AD). Hydrogen sulfide (H2S) has been recognized as a cytoprotectant, which improves learning memory impairment and exerts antioxidant effects in neurodegenerative disorders, including AD. The experiment was projected to explore the effects of H2S on cognitive deficits, Aβ levels and possible antioxidant mechanisms. Here, APP/PS1 transgenic mice were injected sodium hydrosulfide (NaHS, a H2S donor, 2...
November 21, 2016: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/27883331/effects-of-altered-rtn3-expression-on-bace1-activity-and-alzheimer-s-neuritic-plaques
#8
Md Golam Sharoar, Riqiang Yan
Reticulon 3 (RTN3), which is a member of the reticulon family of proteins, has a biochemical function of shaping tubular endoplasmic reticulum. RTN3 has also been found to interact with β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which initiates the generation of β-amyloid peptides (Aβ) from amyloid precursor protein. Aβ is the major proteinaceous component in neuritic plaques, which constitute one of the major pathological features in brains of Alzheimer's disease (AD) patients. Mice deficient in or overexpressing RTN3 have altered amyloid deposition through effects on BACE1 expression and activity...
November 24, 2016: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/27875558/palmitoylated-app-forms-dimers-cleaved-by-bace1
#9
Raja Bhattacharyya, Rebecca H Fenn, Cory Barren, Rudolph E Tanzi, Dora M Kovacs
A major rate-limiting step for Aβ generation and deposition in Alzheimer's disease brains is BACE1-mediated cleavage (β-cleavage) of the amyloid precursor protein (APP). We previously reported that APP undergoes palmitoylation at two cysteine residues (Cys186 and Cys187) in the E1-ectodomain. 8-10% of total APP is palmitoylated in vitro and in vivo. Palmitoylated APP (palAPP) shows greater preference for β-cleavage than total APP in detergent resistant lipid rafts. Protein palmitoylation is known to promote protein dimerization...
2016: PloS One
https://www.readbyqxmd.com/read/27871792/dual-inhibition-of-bace1-and-a%C3%AE-aggregation-by-%C3%AE-ecdysone-application-of-a-phytoecdysteroid-scaffold-in-alzheimer-s-disease-therapeutics
#10
Sandipan Chakraborty, Soumalee Basu
Current medications for the complex neurological disorder, Alzheimer's disease (AD), can neither stop disease progression nor revert back disease pathogenesis. The present study demonstrates the applicability of a phytoecdysteroid, β-ecdysone, as a multi-potent agent in AD therapeutics. β-ecdysone strongly binds to the active site cavity of BACE1 with calculated dissociation constant of 1.75±0.1μM. Steady-state and time-resolved fluorescence spectroscopy reveal that binding of β-ecdysone induces conformational transition of the protein from open to closed form thereby blocking substrate binding...
November 18, 2016: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/27871037/design-synthesis-and-sar-analysis-of-potent-bace1-inhibitors-possible-lead-drug-candidates-for-alzheimer-s-disease
#11
Hamadeh Tarazi, Raed Abu Odeh, Raed Al-Qawasmeh, Imad Abu Yousef, Wolfgang Voelter, Taleb H Al-Tel
We have identified potent isophthalic acid derivatives armed with imidazol and indolyl groups as potent β-secretase inhibitors. The most effective analogs demonstrated low nano-molar potency for the BACE1 (β-secretase cleaving enzyme) as measured by FRET (Fluorescence Resonance Energy Transfer) and cell-based (ELISA) assays. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I...
November 12, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27865910/multi-target-directed-therapeutic-potential-of-7-methoxytacrine-adamantylamine-heterodimers-in-the-alzheimer-s-disease-treatment
#12
Zuzana Gazova, Ondrej Soukup, Vendula Sepsova, Katarina Siposova, Lucie Drtinova, Petr Jost, Katarina Spilovska, Jan Korabecny, Eugenie Nepovimova, Diana Fedunova, Martin Horak, Martina Kaniakova, Ze-Jun Wang, Ayman K Hamouda, Kamil Kuca
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory...
November 16, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27860258/sesamol-supplementation-prevents-systemic-inflammation-induced-memory-impairment-amyloidogenesis-via-inhibition-of-nuclear-factor-kappab
#13
Zhigang Liu, Yuwei Chen, Qinglian Qiao, Yali Sun, Qian Liu, Bo Ren, Xuebo Liu
SCOPE: The aim of the present study was to investigate the inhibitory effects of sesamol, a phenolic lignan from sesame, on the systemic inflammation-induced neuroinflammation and amyloidogenesis as well as memory impairment. METHODS AND RESULTS: C57BL/6J mice were treated with 0.05% sesamol (w/v) in the drinking water for 7 weeks, and then the mice were treated by intraperitoneal injection of LPS (0.25 mg/kg) for 9 days. Sesamol supplementation significantly improved (by 36...
November 15, 2016: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/27858713/protein-expression-of-bace1-is-downregulated-by-donepezil-in-alzheimer-s-disease-platelets
#14
Tamires Alves Sarno, Leda Leme Talib, Helena Passarelli Giroud Joaquim, Jessyka Maria de França Bram, Wagner Farid Gattaz, Orestes Vicente Forlenza
BACKGROUND: Abnormal amyloid-β protein precursor (AβPP) metabolism is a key feature of Alzheimer's disease (AD). Platelets contain most of the enzymatic machinery required for AβPP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, AβPP-related molecules in platelets may be regarded as peripheral markers of AD. OBJECTIVE: We sought to determine the protein expression of the AβPP secretases (ADAM10, BACE1, and PSEN1) and AβPP ratio in platelets of patients with mild or moderate AD compared to healthy controls...
November 14, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27853315/a%C3%AE-42-oligomers-modulate-%C3%AE-secretase-through-an-xbp-1s-dependent-pathway-involving-hrd1
#15
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/27845275/a-hybrid-sirna-delivery-complex-for-enhanced-brain-penetration-and-precise-amyloid-plaque-targeting-in-alzheimer-s-disease-mice
#16
Xiaoyao Zheng, Xiaoying Pang, Peng Yang, Xu Wan, Yue Wei, Qian Guo, Qizhi Zhang, Xinguo Jiang
: To realize the therapeutic potential of gene drugs for Alzheimer's disease (AD), non-invasive, tissue-specific and efficient delivery technologies must be developed. Here, a hybrid system for amyloid plaques targeted siRNA delivery was formed by PEGylated Poly(2-(N,Ndimethylamino) ethyl methacrylate) (PEG-PDMAEMA) conjugated with two d-peptides, a CGN for brain penetration and a QSH for β-amyloid binding. The hybrid complex CQ/siRNA, composed of 25% MPEG-PDMAEMA, 50% CGN-PEG-PDMAEMA and 25% QSH-PEG-PDMAEMA, showed negligible cytotoxicity and could protect siRNA from enzyme degradation...
November 11, 2016: Acta Biomaterialia
https://www.readbyqxmd.com/read/27829662/high-glucose-upregulates-bace1-mediated-a%C3%AE-production-through-ros-dependent-hif-1%C3%AE-and-lxr%C3%AE-abca1-regulated-lipid-raft-reorganization-in-sk-n-mc-cells
#17
Hyun Jik Lee, Jung Min Ryu, Young Hyun Jung, Sei-Jung Lee, Jeong Yeon Kim, Sang Hun Lee, In Koo Hwang, Je Kyung Seong, Ho Jae Han
There is an accumulation of evidence indicating that the risk of Alzheimer's disease is associated with diabetes mellitus, an indicator of high glucose concentrations in blood plasma. This study investigated the effect of high glucose on BACE1 expression and amyloidogenesis in vivo, and we present details of the mechanism associated with those effects. Our results, using ZLC and ZDF rat models, showed that ZDF rats have high levels of amyloid-beta (Aβ), phosphorylated tau, BACE1, and APP-C99. In vitro result with mouse hippocampal neuron and SK-N-MC, high glucose stimulated Aβ secretion and apoptosis in a dose-dependent manner...
November 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27816517/discovery-of-furo-2-3-d-1-3-thiazinamines-as-beta-amyloid-cleaving-enzyme-1-bace1-inhibitors
#18
Yong-Jin Wu, Jason Guernon, Ramkumar Rajamani, Jeremy H Toyn, Michael K Ahlijanian, Charles F Albright, Jodi Muckelbauer, ChiehYing Chang, Dan Camac, John E Macor, Lorin A Thompson
This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.
October 20, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27808264/alzheimer-disease-bace1-inhibition-could-block-csf-tau-increase
#19
Hemi Malkki
No abstract text is available yet for this article.
November 3, 2016: Nature Reviews. Neurology
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
#20
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
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