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Gvido Cebers, Robert C Alexander, Samantha Budd Haeberlein, David Han, Ronald Goldwater, Larry Ereshefsky, Tina Olsson, Naidong Ye, Laura Rosen, Muir Russell, Justine Maltby, Susanna Eketjäll, Alan R Kugler
AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16)...
October 19, 2016: Journal of Alzheimer's Disease: JAD
Kumju Youn, Ji-Hyun Park, Jinhyuk Lee, Woo-Sik Jeong, Chi-Tang Ho, Mira Jun
Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the enzyme involved in the abnormal production of the amyloidogenic peptide Aβ, one of the major causes of histological hallmarks of Alzheimer's disease (AD). Thus, BACE1 represents a key target protein in the development of new potential target for the prevention and treatment of AD. In this study, in vitro anti-AD activity of biochanin A, a dietary isoflavone found in legumes and most notably red clover, were evaluated via human recombinant BACE1 inhibition assay, as well as enzyme kinetic and molecular docking predictions...
October 14, 2016: Nutrients
Carlos Gueto-Tettay, Joshua Zuchniarz, Yeyson Fortich-Seca, Luis Roberto Gueto-Tettay, Juan Carlos Drosos-Ramirez
BACE1 is an aspartyl protease which is a therapeutic target for Alzheimer's disease (AD) because of its participation in the rate-limiting step in the production of Aβ-peptide, the accumulation of which produces senile plaques and, in turn, the neurodegenerative effects associated with AD. The active site of this protease is composed in part by two aspartic residues (Asp93 and Asp289). Additionally, the catalytic site has been found to be covered by an antiparallel hairpin loop called the flap. The dynamics of this flap are fundamental to the catalytic function of the enzyme...
October 7, 2016: Journal of Molecular Graphics & Modelling
Juliane Schelle, Lisa Häsler, Jens C Göpfert, Thomas O Joos, Hugo Vanderstichele, Erik Stoops, Ulf Neumann, Derya R Shimshek, Matthias Staufenbiel, Mathias Jucker, Stephan A Kaeser
INTRODUCTION: The inhibition of the beta-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 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
Wioletta Rozpędek, Dariusz Pytel, J Alan Diehl, Ireneusz Majsterek
Nowadays more than 24 million people suffer from Alzheimer's disease (AD) that is the most common progressive cause of dementia. Molecular mechanisms of neurodegeneration in Alzheimer's disease is closely link with accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER). Deposition of senile plaques is one of the main feature of Alzheimer's disease as well as is strictly correlated with impairment of cognitive abilities. The accumulation of misfolded proteins in the lumen of the ER triggers activation of the ER stress, and subsequently unfolded protein response (UPR) signaling branches, which consists of a cascade of events on the molecular level of nerve cell...
July 29, 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Melanie Hüttenrauch, Susanne Walter, Margie Kaufmann, Sascha Weggen, Oliver Wirths
The environmental enrichment (EE) paradigm is regarded as a useful tool to create a physical and intellectual stimulation for laboratory rodents and has been used in a variety of Alzheimer disease (AD) mouse models. However, the results of these studies have been conflicting as EE had inconsistent effects on memory performance, Aβ deposition, inflammatory status and other pathological outcomes depending on the AD model. Here, we studied the influence of a lifelong EE on the widely used 5XFAD mouse model, representing the main pathological features of AD...
October 12, 2016: Molecular Neurobiology
Andrea M Zuhl, Charles E Nolan, Michael A Brodney, Sherry Niessen, Kevin Atchison, Christopher Houle, David A Karanian, Claude Ambroise, Jeffrey W Brulet, Elizabeth M Beck, Shawn D Doran, Brian T O'Neill, Christopher W Am Ende, Cheng Chang, Kieran F Geoghegan, Graham M West, Joshua C Judkins, Xinjun Hou, David R Riddell, Douglas S Johnson
Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein...
October 11, 2016: Nature Communications
Ma'mon M Hatmal, Shadi Jaber, Mutasem O Taha
Ligand-based pharmacophore modeling require relatively long lists of active compounds, while a pharmacophore based on a single ligand-receptor crystallographic structure is often promiscuous. These problems prompted us to combine molecular dynamics (MD) simulation with ligand-receptor contacts analysis as means to develop valid pharmacophore model(s). The particular ligand-receptor complex is allowed to perturb over a few nano-seconds using MD simulation. Subsequently, ligand-receptor contact points (≤2.5 Å) are identified...
October 8, 2016: Journal of Computer-aided Molecular Design
Dawid Panek, Anna Więckowska, Tomasz Wichur, Marek Bajda, Justyna Godyń, Jakub Jończyk, Kamil Mika, Jana Janockova, Ondrej Soukup, Damijan Knez, Jan Korabecny, Stanislav Gobec, Barbara Malawska
The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0...
September 26, 2016: European Journal of Medicinal Chemistry
Martina Pigoni, Johanna Wanngren, Peer-Hendrik Kuhn, Kathryn M Munro, Jenny M Gunnersen, Hiroshi Takeshima, Regina Feederle, Iryna Voytyuk, Bart De Strooper, Mikail D Levasseur, Brian J Hrupka, Stephan A Müller, Stefan F Lichtenthaler
BACKGROUND: The protease BACE1 (beta-site APP cleaving enzyme) is a major drug target in Alzheimer's disease. However, BACE1 therapeutic inhibition may cause unwanted adverse effects due to its additional functions in the nervous system, such as in myelination and neuronal connectivity. Additionally, recent proteomic studies investigating BACE1 inhibition in cell lines and cultured murine neurons identified a wider range of neuronal membrane proteins as potential BACE1 substrates, including seizure protein 6 (SEZ6) and its homolog SEZ6L...
October 5, 2016: Molecular Neurodegeneration
John Alam, Wiep Scheper
Dysregulated autophagic-lysosomal degradation of proteins has been linked to the most common genetic defect in familial Alzheimer disease, and has been correlated with disease progression in both human disease and in animal models. Recently, it was demonstrated that the expression of MAPK14/p38α protein is upregulated in the brain of APP-PS1 transgenic Alzheimer mouse and further that genetic deficiency of Mapk14 in the APP-PS1 mouse stimulates macroautophagy/autophagy, which then leads to reduced amyloid pathology via increasing autophagic-lysosomal degradation of BACE1...
October 7, 2016: Autophagy
Thomas J Paul, Arghya Barman, Mehmet Ozbil, Ram Prasad Bora, Tingting Zhang, Gaurav Sharma, Zachary Hoffmann, Rajeev Prabhakar
Peptide hydrolysis has been involved in a wide range of biological, biotechnological, and industrial applications. In this perspective, the mechanisms of three distinct peptide bond cleaving enzymes, beta secretase (BACE1), insulin degrading enzyme (IDE), and bovine lens leucine aminopeptidase (BILAP), have been discussed. BACE1 is a catalytic Asp dyad [Asp, Asp(-)] containing aspartyl protease, while IDE and BILAP are mononuclear [Zn(His, His, Glu)] and binuclear [Zn1(Asp, Glu, Asp)-Zn2(Lys, Glu, Asp, Asp)] core possessing metallopeptidases, respectively...
September 14, 2016: Physical Chemistry Chemical Physics: PCCP
Cong Li, Xiao-Dan Guo, Min Lei, Jia-Yi Wu, Jia-Zhen Jin, Xiao-Fan Shi, Zhi-Yuan Zhu, Vatcharin Rukachaisirikul, Li-Hong Hu, Tie-Qiao Wen, Xu Shen
AIM: Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both Aβ level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both Aβ levels and Tau hyperphosphorylation...
October 3, 2016: Acta Pharmacologica Sinica
Zhong-Hao Zhang, Chen Chen, Qiu-Yan Wu, Rui Zheng, Yao Chen, Qiong Liu, Jia-Zuan Ni, Guo-Li Song
Olfactory dysfunction is an early and common symptom in Alzheimer's disease (AD) and is reported to be related to several pathologic changes, including the deposition of Aβ and hyperphosphorylated tau protein as well as synaptic impairment. Selenomethionine (Se-Met), the major form of selenium in animals and humans, may be a promising therapeutic option for AD as it decreases the deposition of Aβ and tau hyperphosphorylation in a triple transgenic mouse model of AD (3× Tg-AD). In this study, 4-month-old AD mice were treated with 6 µg/mL Se-Met in drinking water for 12 weeks and the effect of Se-Met on neuropathological deficits in olfactory bulb (OB) of 3× Tg-AD mice was investigated...
2016: International Journal of Molecular Sciences
Ayano Kimura, Saori Hata, Toshiharu Suzuki
β-site APP-cleaving enzyme 1 (BACE1) cleaves amyloid β protein precursor (APP) at the bond between Met671 and Asp672 (β site) to generate the carboxy-terminal fragment (CTFβ/C99). BACE1 also cleaves APP at another bond between Thy681 and Gln682 (β' site), yielding CTFβ'/C89. Cleavage of CTFβ/C99 by γ-secretase generates Aβ1-XX, whereas cleavage of CTFβ'/C89 generates Aβ11-XX. Thus, β'-site cleavage by BACE1 is amyloidolytic rather than amyloidogenic. β' cleavage of mouse APP is more common than the corresponding cleavage of human APP...
September 29, 2016: Journal of Biological Chemistry
Tokiaki Yamaguchi, Yoshio Yamauchi, Keiko Furukawa, Yuhsuke Ohmi, Yuki Ohkawa, Qing Zhang, Tetsuya Okajima, Koichi Furukawa
Alzheimer's disease (AD) is the most prevalent form of dementia characterized by the extracellular accumulation of amyloid β (Aβ) peptides, which are produced by proteolytic cleavages of amyloid precursor protein (APP). Gangliosides are involved in AD pathophysiology including Aβ deposition and APP processing, yet the detailed mechanisms are not fully understood. Here we examined how changes in the carbohydrate moiety of gangliosides alter APP processing in human melanoma cells, neuroectoderm-derived cells...
September 30, 2016: Scientific Reports
Han-Kyu Lee, Clara Velazquez Sanchez, Mei Chen, Peter J Morin, John M Wells, Eugene B Hanlon, Weiming Xia
The testing of candidate drugs to slow progression of Alzheimer's disease (AD) requires clinical trials that are lengthy and expensive. Efforts to model the biochemical milieu of the AD brain may be greatly facilitated by combining two cutting edge technologies to generate three-dimensional (3D) human neuro-spheroid from induced pluripotent stem cells (iPSC) derived from AD subjects. We created iPSC from blood cells of five AD patients and differentiated them into 3D human neuronal culture. We characterized neuronal markers of our 3D neurons by immunocytochemical staining to validate the differentiation status...
2016: PloS One
Muhammad Zahid Khan, Nagina Atlas, Waqas Nawaz
Cognitive deficiency and oxidative stress have been well documented in aging disorders including Alzheimer's disease. The aim of this study was to investigate the therapeutic efficacy of Caralluma tuberculata methanolic extract (CTME) on cognitive impairment in mice induced with d-galactose. In this study we assessed the therapeutic efficacy of CTME on cognitive impairment in mice induced with d-galactose by conduction of behavioral and cognitive performance tests. In order to explore the possible role of CTME against d-galactose-induced oxidative damages, various biochemical indicators were assessed...
September 23, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Carolyn L Fisher, Ross J Resnick, Soumya De, Lucila A Acevedo, Kun Ping Lu, Frank C Schroeder, Linda K Nicholson
The cis/trans isomerization of X-Pro peptide bonds in proteins in some instances acts as a molecular switch in biological pathways. Our prior work suggests that the cis isomer of the phospho-Thr668-Pro669 motif, located in the cytoplasmic domain of the amyloid-β protein precursor (AβPP), is correlated with an increase in amyloidogenic processing of AβPP and production of amyloid-beta (Aβ), the neurotoxic peptide fragment in Alzheimer's disease (AD). We designed a 100% cis-locked cyclic dipeptide composed of cyclized phospho-Thr-Pro (pCDP) as a mimic for this putative pathological conformation, and three phosphate-blocked derivatives (pCDP-diBzl, pCDP-Bzl, and pCDP-diPOM)...
September 21, 2016: Journal of Alzheimer's Disease: JAD
Fengli Qu, Minghui Yang, Avraham Rasooly
The protease BACE1 (the β-site amyloid precursor protein cleaving enzyme 1) catalyzes the first step in the synthesis of β-amyloids (Aβ), peptides that accumulate in the brain in Alzheimer's disease (AD). Measurement of BACE1 activity is important for the development of BACE1 inhibitors to slow or stop AD. To measure BACE1 cleavage of the electrode-immobilized substrate peptide, we developed a redox-generating hydroxyapatite (HAP) probe which generates electrochemical current by reaction of the nanoparticle with molybdate (MoO4(2-))...
October 17, 2016: Analytical Chemistry
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