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https://www.readbyqxmd.com/read/29352484/melatonin-ameliorates-a%C3%AE-42-induced-alteration-of-%C3%AE-app-processing-secretases-via-the-melatonin-receptor-through-the-pin1-gsk3%C3%AE-nf-%C3%AE%C2%BAb-pathway-in-sh-sy5y-cells
#1
Vorapin Chinchalongporn, Mayuri Shukla, Piyarat Govitrapong
Melatonin is involved in the physiological regulation of the β- amyloid precursor protein (βAPP) cleaving secretases which are responsible for generation of the neurotoxic amyloid beta (Aβ) peptide, one of the hallmarks of Alzheimer's disease (AD) pathology. In this study, we aimed to determine the underlying mechanisms of this regulation under pathological conditions. We establish that melatonin prevents Aβ42 -induced down-regulation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) as well as up-regulation of β-site APP-cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) in SH-SY5Y cell cultures...
January 20, 2018: Journal of Pineal Research
https://www.readbyqxmd.com/read/29348391/effects-of-senescence-and-angiotensin-ii-on-expression-and-processing-of-amyloid-precursor-protein-in-human-cerebral-microvascular-endothelial-cells
#2
Ruohan Sun, Tongrong He, Yujun Pan, Zvonimir S Katusic
The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, β-site APP cleaving enzyme (BACE1) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aβ generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression...
January 15, 2018: Aging
https://www.readbyqxmd.com/read/29341888/protection-against-the-neurotoxic-effects-of-%C3%AE-amyloid-peptide-on-cultured-neuronal-cells-by-lovastatin-involves-elevated-expression-of-%C3%AE-7-nicotinic-acetylcholine-receptors-and-activating-phosphorylation-of-protein-kinases
#3
Liang Zhao, Yan Xiao, Jin Xiu, Long-Chun Tan, Zhi-Zhong Guan
The treatment of neurodegenerative diseases with statins has drawn increasing attention, but the related molecular mechanisms remain elusive. To examine the pleiotropic cholesterol-independent effects of statins in connection with the treatment of Alzheimer disease, we probed the influence of lovastatin on the metabolism of amyloid precursor protein (APP) , expression of nicotinic acetylcholine receptors (nAChRs), and activity of mitogen-activated protein kinase in primary cultured neurons and SH-SY5Y cells over-expressing human APP670/671...
January 13, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29332584/multicomponent-reactions-for-multitargeted-compounds-for-alzheimer-s-disease
#4
Lhassane Ismaili, Maria do Carmo Carreiras
Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder affecting around 35 million people worldwide, which is characterized by decline of cholinergic function, deregulation of amyloid beta (Aβ) oligomers formation and Aβ fibril deposition. Multi-target--directed ligands (MTDLs) have emerged as an original strategy for developing new therapeutic agents on AD. Multicomponent reactions (MCRs) are a useful alternative to sequential multistep syntheses, allowing scaffold diversity and a rapid and easy access to biologically relevant compounds...
January 12, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29331531/profiles-of-%C3%AE-amyloid-peptides-and-key-secretases-in-brain-autopsy-samples-differ-with-sex-and-apoe-%C3%AE%C2%B54-status-impact-for-risk-and-progression-of-alzheimer-disease
#5
Jennifer N K Nyarko, Maa O Quartey, Paul R Pennington, Ryan M Heistad, Doris Dea, Judes Poirier, Glen B Baker, Darrell D Mousseau
The APOE ε 4 allele was originally reported to contribute to risk of Alzheimer disease (AD) in women, yet male and female AD patient-derived data are routinely pooled. Histopathological hallmarks of AD include neurofibrillary tangles centered on hyperphosphorylated Tau and plaques composed of the β -amyloid (A β) peptide that is derived by sequential secretase-mediated cleavage of the Amyloid Protein Precursor (APP). We chose to examine profiles of A β (1-40), A β (1-42), and N-truncated (i.e. p3-related) fragments in the plaque-associated fraction of autopsied cortical and corresponding hippocampal samples from donors with a diagnosis of early-onset (EOAD) and late-onset (LOAD) AD...
January 10, 2018: Neuroscience
https://www.readbyqxmd.com/read/29327496/modulation-of-bace1-activity-by-chemically-modified-aptamers
#6
Cécile Gasse, Marwa Zaarour, Sam Noppen, Mikhail Abramov, Philippe Marlière, Sandra Liekens, Bart De Strooper, Piet Herdewijn
A modified DNA aptamer was developed that binds BACE1, a therapeutic target involved in Alzheimer's disease. This ssXNA not only tightly binds to BACE1 but also inhibits its protease activity in vitro in the same range as a previously described unmodified aptamer. We report the in vitro selection of functional oligonucleotides using two nucleobase modifications: 5-chlorouracil and 7-deazaadenine. The nucleoside analog 5-chloro-2'-deoxyuridine has already been explored to replace thymidine in a chemically modified genome of a bacterium...
January 11, 2018: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29327084/bace1-inhibition-more-effectively-suppresses-initiation-than-progression-of-%C3%AE-amyloid-pathology
#7
Finn Peters, Hazal Salihoglu, Eva Rodrigues, Etienne Herzog, Tanja Blume, Severin Filser, Mario Dorostkar, Derya R Shimshek, Nils Brose, Ulf Neumann, Jochen Herms
BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early β-amyloid pathology...
January 11, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29325091/%C3%AE-secretase-adam10-physically-interacts-with-%C3%AE-secretase-bace1-in-neurons-and-regulates-chl1-proteolysis
#8
Xin Wang, Congcong Wang, Gang Pei
α-secretase and β-secretase are known to compete for amyloid precursor protein (APP) processing and thus play a vital role in Alzheimer's disease pathogenesis. A disintegrin and metalloproteinase 10 (ADAM10) and β-site APP cleaving enzyme 1 (BACE1) mediate the major activities of α-secretase and β-secretase in brain and share various common substrates. However, whether they function separately or together is poorly understood. Here, we show that ADAM10 and BACE1 co-localize in the neurites of mouse primary neurons...
January 9, 2018: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29319935/clinical-bioavailability-of-the-novel-bace1-inhibitor-lanabecestat-azd3293-assessment-of-tablet-formulations-versus-an-oral-solution-and-the-impact-of-gastric-ph-on-pharmacokinetics
#9
Naidong Ye, Scott A Monk, Pankaj Daga, David M Bender, Laura B Rosen, Jamie Mullen, Margaret C Minkwitz, Alan R Kugler
The relative bioavailability of lanabecestat administered as 2 tablet formulations versus an oral solution was investigated. This phase 1 single-center, open-label, randomized, 3-period crossover study involved healthy male and nonfertile female subjects aged 18-55 years (NCT02039180). Subjects received a single 50-mg lanabecestat dose as solution, tablet A, or tablet B on day 1 of each crossover period; 14 of 16 subjects completed the study. Relative bioavailability based on plasma lanabecestat AUC0-∞ (area under the plasma drug concentration-time curve from zero to infinity) geometric mean ratio versus oral solution (primary variable) was: tablet A, 1...
January 10, 2018: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29316899/plasma-long-non-coding-rna-bace1-as-a-novel-biomarker-for-diagnosis-of-alzheimer-disease
#10
Liang Feng, Yu-Ting Liao, Jin-Cai He, Cheng-Long Xie, Si-Yan Chen, Hui-Hui Fan, Zhi-Peng Su, Zhen Wang
BACKGROUNDS: Long non-coding RNA (LncRNA) have been reported to be involved in the pathogenesis of neurodegenerative diseases, but whether it can serve as a biomarker for Alzheimer disease (AD) is not yet known. METHODS: The present study selected four specific LncRNA (17A, 51A, BACE1 and BC200) as possible AD biomarker. RT-qPCR was performed to validate the LncRNA. Receiver operating characteristic curve (ROC) and area under the ROC curve (AUC) were applied to study the potential of LncRNA as a biomarker in a population of 88 AD patients and 72 control individuals...
January 9, 2018: BMC Neurology
https://www.readbyqxmd.com/read/29315574/palmitate-induced-c-ebp-homologous-protein-activation-leads-to-nf-%C3%AE%C2%BAb-mediated-increase-in-bace1-activity-and-amyloid-beta-genesis
#11
Gurdeep Marwarha, Jared Schommer, Jonah Lund, Trevor Schommer, Othman Ghribi
The etiology of Alzheimer's disease (AD) is egregiously comprehended, but epidemiological studies have posited that diets rich in the saturated fatty acid palmitic acid (palmitate) are a significant risk factor. The production and accumulation of Amyloid-beta peptide (Aβ) is considered the core pathological molecular event in the pathogenesis of AD. The rate limiting step in Aβ genesis from Amyloid-β precursor protein (AβPP) is catalyzed by the enzyme β-site APP cleaving enzyme 1 (BACE1), the expression and enzymatic activity of which is significantly upregulated in the AD brain...
January 6, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29311632/bace1-dependent-amyloid-processing-regulates-hypothalamic-leptin-sensitivity-in-obese-mice
#12
Paul J Meakin, Susan M Jalicy, Gemma Montagut, David J P Allsop, Daniella L Cavellini, Stuart W Irvine, Christopher McGinley, Mary K Liddell, Alison D McNeilly, Karolina Parmionova, Yu-Ru Liu, Charlotte L S Bailey, J Kim Dale, Lora K Heisler, Rory J McCrimmon, Michael L J Ashford
Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ1-42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29310523/docking-molecular-dynamics-binding-energy-mm-pbsa-studies-of-naphthofuran-derivatives-to-identify-potential-dual-inhibitors-against-bace-1-and-gsk-3%C3%AE
#13
Akhil Kumar, Gaurava Srivastava, Arvind S Negi, Ashok Sharma
BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer's disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (triazinone and curcumin) derivatives have been reported as BACE-1 and GSK-3β dual inhibitors. In our previous work, we have reported first in class dual inhibitor for BACE-1 and GSK-3β. In this study we have explored other naphthofuran derivatives for their potential to inhibit BACE-1 and GSK-3β through docking, molecular dynamics, binding energy (MM-PBSA)...
January 8, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29301478/new-substituted-aminopyrimidine-derivatives-as-bace1-inhibitors-in-silico-design-synthesis-and-biological-assays
#14
Lucas J Gutiérrez, Oscar Parravicini, Emilse Sánchez, Ricaurte Rodríguez, Justo Cobo, Ricardo D Enriz
We report in this work new substituted aminopyrimidine derivatives acting as inhibitors of the catalytic site of BACE1. These compounds were obtained from a molecular modelling study. The theoretical and experimental study reported here was carried out in several steps: docking analysis, Molecular Dynamics (MD) simulations, Quantum Theory Atom in Molecules (QTAIM) calculations, synthesis and bioassays and has allowed us to propose some compounds of this series as new inhibitors of the catalytic site of BACE1...
January 4, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29301410/factors-influencing-the-potency-of-alzheimer-inhibitors-computational-and-docking-studies
#15
Faten Atlam, Mohamed Awad, Rehab Salama
Density functional theory (B3LYP/6-31G [d]) is performed to study the effect of molecular and electronic structures of the investigated β-secretase 1 (BACE1) Alzheimer's inhibitors on their biological activities and discuss the correlation between their inhibition efficiencies and quantum chemical descriptors. IC50 values of the investigated compounds are mostly affected by the substituted R2 phenyl moiety. The calculations show that the presence of electron withdrawing group increases the half maximal inhibitory concentration (IC50)...
January 1, 2018: American Journal of Alzheimer's Disease and Other Dementias
https://www.readbyqxmd.com/read/29283428/structure-related-inhibition-of-enzyme-systems-in-cholinesterases-and-bace1-in-vitro-by-naturally-occurring-naphthopyrone-and-its-glycosides-isolated-from-cassia-obtusifolia
#16
Srijan Shrestha, Su Hui Seong, Pradeep Paudel, Hyun Ah Jung, Jae Sue Choi
Cassia obtusifolia Linn. have been used to improve vision, inflammatory diseases, and as hepatoprotective agents and to promote urination from ancient times. In the present study, we investigated the influence of glycosylation of components of C. obtusifolia and structure-activity relationships (SARs) with respect to the inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), which are related to Alzheimer's disease (AD)...
December 28, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29275517/sarsasapogenin-suppresses-a%C3%AE-overproduction-induced-by-high-glucose-in-ht-22-cells
#17
Meng-Ya Zhang, Yu Li, Shen-Yuan Yin, Li Kong, Xiao-Li Liu, Xiao-Xing Yin, Yao-Wu Liu
The aim of this study is to investigate effects and potential mechanisms of sarsasapogenin (Sar), an active component purified from Rhizoma Anemarrhenae, on high glucose-induced amyloid-beta (Aβ) peptide overproduction in HT-22 cells. HT-22 cells were divided into normal glucose; high glucose (HG); HG co-treated with low, middle, and high concentration of Sar (1, 5, 25 μmol/L); and peroxisome proliferator-activated receptor γ (PPARγ) agonist (10 μmol/L pioglitazone). After treatment for 24 h, protein expression of Aβ and β-site Aβ precursor protein cleaving enzyme 1 (BACE1) and activated PPARγ level were determined by Western blot; Aβ42 levels were also measured by using both immunofluorescence and ELISA methods...
December 23, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/29248542/toluidine-blue-o-modifies-hippocampal-amyloid-pathology-in-a-transgenic-mouse-model-of-alzheimer-s-disease
#18
Melike Yuksel, Kevser Biberoglu, Seda Onder, K Gonca Akbulut, Ozden Tacal
Recently, we demonstrated that toluidine blue O (TBO), a phenothiazine dye, shows inhibitory effects on both cholinesterases and amyloid pathology in Alzheimer's disease (AD) cellular model. In the present study, we aimed to determine the effects of TBO (in a purity of 85%) on amyloid and tau pathologies in a triple transgenic mouse model of AD (3xTg-AD). Beginning at 7.5 (mild pathology) or 13 (severe pathology) months of age, 3xTg-AD mice were treated intraperitoneally with 4 mg/kg TBO or vehicle daily for 30 days...
December 14, 2017: Biochimie
https://www.readbyqxmd.com/read/29246793/long-term-treadmill-exercise-attenuates-a%C3%AE-burdens-and-astrocyte-activation-in-app-ps1-mouse-model-of-alzheimer-s-disease
#19
Jing Zhang, Yunliang Guo, Yongxiang Wang, Lin Song, Rui Zhang, Yifeng Du
Alzheimer's disease (AD) is a devastating disease characterized with progressive neurodegenerative disorders in the elderly. Epidemiological and clinical studies reported that lifestyle factors could halt the progression of AD, especially physical exercise. In the present work, we investigated the effects of long-term treadmill exercise on the pathological cascades of AD in APP/PS1 mice. After exercise for 5 months, Aβ deposition was significantly ameliorated in terms of Aβ area fraction, plaque number and size...
December 12, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29245901/nav%C3%AE-2-knockdown-improves-cognition-in-app-ps1-mice-by-partially-inhibiting-seizures-and-app-amyloid-processing
#20
Tao Hu, Zhangang Xiao, Rui Mao, Bo Chen, Min-Nan Lu, Jun Tong, Rong Mei, Shan-Shan Li, Zhi-Cheng Xiao, Lian-Feng Zhang, Yan-Bin Xiyang
Voltage-gated sodium channels beta 2 (Navβ2, encoded by SCN2B) is a substrate of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and regulates cell surface expression of channels in neurons. Previous studies reported enhanced Navβ2 processing by BACE1 in Alzheimer's disease (AD) model and patients. We investigated whether changes in Navβ2 expression affect neuronal seizure and amyloid precursor protein (APP) processing in an AD mouse model. Our study used eight-month-old APP/presenilin 1 (PS1) mice and transgenic Navβ2 knockdown [by 61% vs...
November 21, 2017: Oncotarget
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