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https://www.readbyqxmd.com/read/28641077/inhibition-of-early-growth-response-1-in-the-hippocampus-alleviates-neuropathology-and-improves-cognition-in-an-alzheimer-model-with-plaques-and-tangles
#1
Xike Qin, Yunling Wang, Hemant K Paudel
A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, amyloid-β (Aβ) pathology, and improves cognition in the 3xTg-AD mouse model...
June 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28632395/design-synthesis-and-multitarget-biological-profiling-of-second-generation-anti-alzheimer-rhein-huprine-hybrids
#2
Francisco Javier Pérez-Areales, Nibal Betari, Antonio Viayna, Caterina Pont, Alba Espargaró, Manuela Bartolini, Angela De Simone, José Fernando Rinaldi Alvarenga, Belén Pérez, Raimon Sabate, Rosa Maria Lamuela-Raventós, Vincenza Andrisano, Francisco Javier Luque, Diego Muñoz-Torrero
AIM: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. MATERIALS & METHODS: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Aβ42 and tau aggregation, of antioxidant activity, and of brain permeation...
June 20, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28627692/the-role-of-intestinal-endotoxemia-in-a-rat-model-of-aluminum-neurotoxicity
#3
Feng Wang, Rui-Xia Guo, Wen-Xing Li, Bao-Feng Yu, Bai Han, Li-Xin Liu, De-Wu Han
The present study aimed to investigate the effects of intestinal endotoxemia (IETM) in a rat model of aluminum neurotoxicity established by D-galactose and aluminum trichloride (AlCl3). Adult Wistar rats were administered D‑galactose and AlCl3 to create the aluminum neurotoxicity model. The learning and memory abilities of the rats were subsequently observed using a Morris water maze test and the serum levels of lipopolysaccharide (LPS), tumor necrosis factor (TNF)‑α, interleukin (IL)‑1, diamine oxidase (DAO), glutamine (Gln) and glutaminase were measured...
June 15, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28626017/amyloid-beta-peptide-is-needed-for-cgmp-induced-long-term-potentiation-and-memory
#4
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/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/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
#6
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/28593394/double-balloon-assisted-coil-embolization-bace-combined-with-proximal-and-distal-balloon-inflation-for-short-abdominal-arterial-segments-comparison-with-single-bace
#7
Mitsunari Maruyama, Takeshi Yoshizako, Tomonori Nakamura, Megumi Nakamura, Rika Yoshida, Shinji Ando, Hajime Kitagaki
PURPOSE: To evaluate the differences of technique between coil embolization for short abdominal arterial segments with only proximal balloon inflation and combined proximal and distal balloon inflation, as well as the volume embolization ratio (VER) and the ratio of the first coil diameter to the target vessel diameter (first coil diameter ratio). MATERIALS AND METHODS: From January 2014 to August 2016, we performed coil embolization of the short segment in seven patients...
June 7, 2017: Cardiovascular and Interventional Radiology
https://www.readbyqxmd.com/read/28568844/effect-of-sampling-on-bace-1-ligands-binding-free-energy-predictions-via-mm-pbsa-calculations
#8
Nicolas Chéron, Eugene I Shakhnovich
The BACE-1 enzyme is a prime target to find a cure to Alzheimer's disease. In this article, we used the MM-PBSA approach to compute the binding free energies of 46 reported ligands to this enzyme. After showing that the most probable protonation state of the catalytic dyad is mono-protonated (on ASP32), we performed a thorough analysis of the parameters influencing the sampling of the conformational space (in total, more than 35 μs of simulations were performed). We show that ten simulations of 2 ns gives better results than one of 50 ns...
June 1, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28559896/climate-influences-the-content-and-chemical-composition-of-foliar-tannins-in-green-and-senesced-tissues-of-quercus-rubra
#9
Sara M Top, Caroline M Preston, Jeffrey S Dukes, Nishanth Tharayil
Environmental stresses not only influence production of plant metabolites but could also modify their resorption during leaf senescence. The production-resorption dynamics of polyphenolic tannins, a class of defense compound whose ecological role extends beyond tissue senescence, could amplify the influence of climate on ecosystem processes. We studied the quantity, chemical composition, and tissue-association of tannins in green and freshly-senesced leaves of Quercus rubra exposed to different temperature (Warming and No Warming) and precipitation treatments (Dry, Ambient, Wet) at the Boston-Area Climate Experiment (BACE) in Massachusetts, USA...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28534925/osmotin-loaded-magnetic-nanoparticles-with-electromagnetic-guidance-for-the-treatment-of-alzheimer-s-disease
#10
Faiz Ul Amin, Ali Kafash Hoshiar, Ton Duc Do, Yeongil Noh, Shahid Ali Shah, Muhammad Sohail Khan, Jungwon Yoon, Myeong Ok Kim
Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregated amyloid beta (Aβ) in the brain. Here, we describe for the first time the development of a new, pioneering nanotechnology-based drug delivery approach for potential therapies for neurodegenerative diseases, particularly AD. We demonstrated the delivery of fluorescent carboxyl magnetic Nile Red particles (FMNPs) to the brains of normal mice using a functionalized magnetic field (FMF) composed of positive- and negative-pulsed magnetic fields generated by electromagnetic coils...
May 23, 2017: Nanoscale
https://www.readbyqxmd.com/read/28520620/-epigallocatechin-3-gallate-ameliorates-memory-impairment-and-rescues-the-abnormal-synaptic-protein-levels-in-the-frontal-cortex-and-hippocampus-in-a-mouse-model-of-alzheimer-s-disease
#11
Yufang Guo, Yan Zhao, Ying Nan, Xiang Wang, Yulong Chen, Shuang Wang
(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic extract in green tea and it has attracted increasing attention for its multiple bioactive effects. However, the mechanisms by which EGCG exerts its neuroprotective actions in Alzheimer's disease (AD) are presently lacking. In the present study, a sporadic AD transgenic mouse model known as senescence-accelerated mouse prone 8 (SAMP8) was used to investigate whether oral administration of EGCG could improve recognition and memory function through reduction of amyloid β (Aβ) and tau hyperphosphorylation...
July 5, 2017: Neuroreport
https://www.readbyqxmd.com/read/28505196/unveiling-a-novel-transient-druggable-pocket-in-bace-1-through-molecular-simulations-conformational-analysis-and-binding-mode-of-multisite-inhibitors
#12
Ornella Di Pietro, Jordi Juárez-Jiménez, Diego Muñoz-Torrero, Charles A Laughton, F Javier Luque
The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer's disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challenging. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments-huprine and rhein-that individually are endowed with very low activity against BACE-1...
2017: PloS One
https://www.readbyqxmd.com/read/28499972/simvastatin-ameliorates-memory-impairment-and-neurotoxicity-in-streptozotocin-induced-diabetic-mice
#13
Shun-Chang Fang, Hang Xie, Fang Chen, Mei Hu, Yan Long, Hong-Bin Sun, Ling-Yi Kong, Hao Hong, Su-Su Tang
Diabetes comes with an additional burden of moderate to severe hyperlipidemia, but little is known about the effects of lipid-lowering therapy on diabetic complications such as diabetes-associated cognitive decline. Herein we investigated the effects of statins on memory impairment and neurotoxicity in streptozotocin-induced diabetic mice. Our data indicated that oral administration of simvastatin at 10 or 20mg/kg for 4weeks significantly ameliorated diabetes-associated memory impairment reflected by performance better in the Morris water maze and Y-maze tests...
May 10, 2017: Neuroscience
https://www.readbyqxmd.com/read/28469554/physiological-functions-of-the-%C3%AE-site-amyloid-precursor-protein-cleaving-enzyme-1-and-2
#14
REVIEW
Riqiang Yan
BACE1 was discovered as the β-secretase for initiating the cleavage of amyloid precursor protein (APP) at the β-secretase site, while its close homology BACE2 cleaves APP within the β-amyloid (Aβ) domain region and shows distinct cleavage preferences in vivo. Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer's disease therapy. While BACE1 inhibitors are being tested in advanced clinical trials, knowledge regarding the properties and physiological functions of BACE is highly important and this review summarizes advancements in BACE1 research over the past several years...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28460142/comparative-proteomics-reveals-silver-nanoparticles-alter-fatty-acid-metabolism-and-amyloid-beta-clearance-for-neuronal-apoptosis-in-a-triple-cell-co-culture-model-of-the-blood-brain-barrier
#15
Ho-Chen Lin, Ming-Yi Ho, Chao-Ming Tsen, Chien-Chu Huang, Chin-Ching Wu, Yuh-Jeen Huang, I-Lun Hsiao, Chun-Yu Chuang
Silver nanoparticles (AgNPs) enter the central nervous system through the blood-brain barrier (BBB). AgNP exposure can increase amyloid beta (Aβ) deposition in neuronal cells to potentially induce Alzheimer disease (AD) progression. However, the mechanism through which AgNPs alter BBB permeability in endothelial cells and subsequently lead to AD progression remains unclear. This study investigated whether AgNPs disrupt the tight junction proteins of brain endothelial cells, and alter the proteomic metabolism of neuronal cells underlying AD progression in a triple cell co-culture model constructed using mouse brain endothelial (bEnd...
April 29, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28450540/aplp1-is-a-synaptic-cell-adhesion-molecule-supporting-maintenance-of-dendritic-spines-and-basal-synaptic-transmission
#16
Sandra Schilling, Annika Mehr, Susann Ludewig, Jonathan Stephan, Marius Zimmermann, Alexander August, Paul Strecker, Martin Korte, Edward H Koo, Ulrike C Müller, Stefan Kins, Simone Eggert
The amyloid precursor protein (APP), a key player in Alzheimer's disease, belongs to the family of synaptic adhesion molecules (SAMs) due to its impact on synapse formation and synaptic plasticity. These functions are mediated by both the secreted APP ectodomain that acts as a neurotrophic factor and full-length APP forming trans-cellular dimers. Two homologs of APP exist in mammals: the APP like proteins APLP1 and APLP2, exhibiting functions that partly overlap with those of APP. Here we tested whether APLP1 and APLP2 also show features of SAMs...
May 24, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28432142/structural-similarities-between-neuregulin-1-3-isoforms-determine-their-subcellular-distribution-and-signaling-mode-in-central-neurons
#17
Detlef Vullhorst, Tanveer Ahmad, Irina Karavanova, Carolyn Keating, Andres Buonanno
The Neuregulin (NRG) family of ErbB ligands is comprised of numerous variants originating from the use of different genes, alternative promoters, and splice variants. NRGs have generally been thought to be transported to axons and presynaptic terminals where they signal via ErbB3/4 receptors in paracrine or juxtacrine mode. However, we recently demonstrated that unprocessed pro-NRG2 accumulates on cell bodies and proximal dendrites, and that NMDAR activity is required for shedding of its ectodomain by metalloproteinases...
May 24, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28427814/design-synthesis-and-x-ray-structural-studies-of-bace-1-inhibitors-containing-substituted-2-oxopiperazines-as-p1-p2-ligands
#18
Arun K Ghosh, Margherita Brindisi, Yu-Chen Yen, Emilio L Cárdenas, Jean-Rene Ella-Menye, Nagaswamy Kumaragurubaran, Xiangping Huang, Jordan Tang, Andrew D Mesecar
We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1' and P2' ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki=2nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated...
June 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28427163/the-application-of-is6110-baced-loop-mediated-isothermal-amplification-lamp-in-the-early-diagnosis-of-tuberculous-meningitis
#19
Wen-Wen Sun, Qin Sun, Li-Ping Yan, Qing Zhang
Here, we evaluated the potential activity of rapid Mycobacterium tuberculosis detection with loop-mediated isothermal amplification (LAMP), for the early diagnosis of tuberculous meningitis (TBM). Patients with suspected TBM from January 2014 to December 2015 were reviewed retrospectively. The cerebrospinalfluid(CSF) was collected. Acid-fast bacillus (AFB) staining, MGIT 960 culture, real-time fluorescent quantitative polymerase chain reaction (RTFQ PCR) and LAMP were performed. A total of 200 patients were included in the study...
February 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28413992/screening-and-elucidation-of-selected-natural-compounds-for-anti-alzheimer-s-potential-targeting-bace-1-enzyme-a-case-computational-study
#20
Syed Sayeed Ahmad, Salman Akhtar, Syed Mohd Danish Rizvi, Mohammad A Kamal, Usman Sayeed, Mohd Kalim A Khan, Mohd Haris Siddiqui, Jamal M Arif
BACKGROUND: The present study clarifies the molecular interactions of human BACE1 with novel natural ligands and also with the well-known ligand 2, 2, 4-trihydroxychalcone and Galangin for comparison. OBJECTIVE: The study of enzyme- ligands interaction is interest, description of ligands binding to the active site of target molecule could be beneficial to better understanding the mechanism of the ligand on the target molecule. METHOD: Lipinski rule of five, and docking study was performed between ligands and enzyme using 'Autodock4...
April 14, 2017: Current Computer-aided Drug Design
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