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Wenyu Jiao, Yongchen Wang, Linghong Kong, Tao Ou-Yang, Qing Meng, Qiang Fu, Zhenzhen Hu
The accumulation of amyloid-beta (Aβ) and oxidative stress damage in the brain are recognized as early features of Alzheimer's disease (AD). The cocaine- and amphetamine-regulated transcript (CART) peptide may possibly play an antioxidative role in neurons. The aim of this study was to investigate the potential antioxidant mechanism of CART peptide in a rat model of AD. We microinjected of Aβ1-42 (2μl/4μg/hemisphere) into rat hippocampus to set a rat model of AD. A pre-microinjection of CART peptide (1μl/0...
May 16, 2018: Biochemical and Biophysical Research Communications
Vinothkumar G, Krishnakumar S, Sureshkumar, Shivashekar G, Sreedhar S, Preethikrishnan, Dinesh S, Sundaram A, Balakrishnan D, Riya, Venkataraman P
BACKGROUND: Cognitive dysfunction is reported to be a major cause of morbidity in chronic kidney disease (CKD). The senile plaques (SPs) in the brain are one of the most pathophysiological characteristics of cognitive dysfunction and its major constituent amyloid β (Aβ) released from amyloid precursor protein (APP) by β (BACE1) and γ (presenilin 1) secretases . Platelets contain more than 95% of the circulating APP and implicate as a candidate biomarker for cognitive decline. Recombinant human erythropoietin (rHuEPO) is a standard therapy for anemia in CKD and also acts as a neuroprotective agent...
May 14, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Kenji Nakahara, Kouki Fuchino, Kazuo Komano, Naoya Asada, Genta Tadano, Tsuyoshi Hasegawa, Takahiko Yamamoto, Yusuke Sako, Masayoshi Ogawa, Chie Unemura, Motoko Hosono, Hisanori Ito, Gaku Sakaguchi, Shigeru Ando, Shuichi Ohnishi, Yasuto Kido, Tamio Fukushima, Deborah Dhuyvetter, Herman Borghys, Harrie J M Gijsen, Yoshinori Yamano, Yasuyoshi Iso, Ken-Ichi Kusakabe
β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analog of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition...
May 18, 2018: Journal of Medicinal Chemistry
Shuangshuang Xie, Ye Wu, Yuben Qiao, Yi Guo, Jianping Wang, Zhengxi Hu, Qing Zhang, Xiaonian Li, Jinfeng Huang, Qun Zhou, Zengwei Luo, Junjun Liu, Hucheng Zhu, Yongbo Xue, Yonghui Zhang
To explore the chemical diversity of metabolites from endophytic fungi, the strain Phomopsis sp. TJ507A, isolated from the medicinal plant Phyllanthus glaucus, was investigated. A 2,3- seco-protoilludane-type sesquiterpenoid (1), eight protoilludane-type sesquiterpenoids (2-9), four illudalane-type sesquiterpenoids (10a/10b, 11, and 12), and a botryane-type sesquiterpenoid (13) in addition to seven known sesquiterpenoids (14-20) were identified from the liquid culture of the fungus. Structures of the isolated compounds, including their absolute configurations, were elucidated based on extensive spectroscopic analyses, a modified Mosher analysis, electronic circular dichroism (ECD) calculations, and [Rh2 (OCOCF3 )4 ]-induced ECD spectra as well as X-ray crystallographic analyses...
May 17, 2018: Journal of Natural Products
Maria A Tikhonova, Tamara G Amstislavskaya, Victor M Belichenko, Larisa A Fedoseeva, Sergey P Kovalenko, Ekaterina E Pisareva, Alla S Avdeeva, Nataliya G Kolosova, Nikolai D Belyaev, Lyubomir I Aftanas
BACKGROUND: The dominant hypothesis about the pathogenesis of Alzheimer's disease (AD) is the "amyloid cascade" concept and modulating the expression of proteins involved in the metabolism of amyloid-beta (Aβ) is proposed as an effective strategy for the prevention and therapy of AD. Recently, we found that an antibiotic ceftriaxone (CEF), which possesses neuroprotective activity, reduced cognitive deficits and neurodegenerative changes in OXYS rats, a model of sporadic AD...
April 19, 2018: BMC Neuroscience
Ioannis Dafnis, Christina Raftopoulou, Christina Mountaki, Evgenia Megalou, Vassilis I Zannis, Angeliki Chroni
The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates the production of amyloid-beta peptide (Aβ) which is central to the pathogenesis of Alzheimer's disease (AD). Changes in brain cholesterol homeostasis have been suggested to affect Aβ metabolism. Cholesterol homeostasis is maintained in the brain by apolipoprotein E (apoE). The apoE4 isoform constitutes the major risk factor for AD. Here, we investigated the effect of apoE forms on Aβ generation and on BACE1 levels. We also examined the potential involvement in these processes of cholesterol transporters ABCG1 and ABCG4 or the lipoprotein receptor SR-BI that are implicated in cholesterol efflux to apoE...
May 9, 2018: Biochemical Journal
Ying Du, Yingjun Zhao, Chuan Li, Qiuyang Zheng, Jing Tian, Zhuyi Li, Timothy Y Huang, Wei Zhang, Huaxi Xu
β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aβ degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain...
May 8, 2018: Journal of Experimental Medicine
Kouki Fuchino, Yasunori Mitsuoka, Moriyasu Masui, Noriyuki Kurose, Shuhei Yoshida, Kazuo Komano, Takahiko Yamamoto, Masayoshi Ogawa, Chie Unemura, Motoko Hosono, Hisanoro Ito, Gaku Sakaguchi, Shigeru Ando, Shuichi Ohnishi, Yasuto Kido, Tamio Fukushima, Hirofumi Miyajima, Shuichi Hiroyama, Kiyotaka Koyabu, Deborah Dhuyvetter, Herman Borghys, Harrie J M Gijsen, Yoshinori Yamano, Yasuyoshi Iso, Ken-Ichi Kusakabe
Accumulation of Aβ peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. β-Secretase (BACE1) is a key enzyme responsible for producing Aβ peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydo-oxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a pKa lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aβ reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models...
May 7, 2018: Journal of Medicinal Chemistry
Julia Herber, Jasenka Njavro, Regina Feederle, Ute Schepers, Ulrike Müller, Stefan Bräse, Stephan Müller, Stefan F Lichtenthaler
The cell surface proteome is dynamic and has fundamental roles in cell signaling. Many surface membrane proteins are proteolytically released into a cell's secretome, where they can have additional functions in cell-cell-communication. Yet, it remains challenging to determine the surface proteome and to compare it to the cell secretome, in particular under serum-containing cell culture conditions. Here, we set-up and evaluated the 'surface-spanning protein enrichment with click sugars' (SUSPECS) method for cell surface membrane glycoprotein biotinylation, enrichment and label-free quantitative mass spectrometry...
May 1, 2018: Molecular & Cellular Proteomics: MCP
Yacoubou Abdoul Razak Mahaman, Fang Huang, Mengjuan Wu, Yuman Wang, Zhen Wei, Jian Bao, Maibouge Tanko Mahamane Salissou, Dan Ke, Qun Wang, Rong Liu, Jian-Zhi Wang, Bin Zhang, Dan Chen, Xiaochuan Wang
Alzheimer's disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats...
April 28, 2018: Journal of Alzheimer's Disease: JAD
Hongwei Guo, Deyu Xia, Shaohua Liao, Bing Niu, Jigang Tang, Huaiqiang Hu, Hairong Qian, Bingzhen Cao
Alzheimer's disease (AD) is primarily characterized by the production and deposit of β-amyloid protein (Aβ) in β-amyloid plaques (APs). On this basis, we investigated whether vascular endothelial growth factor (VEGF), a growth factor with important neuroprotective activity, may provide a therapeutic opportunity for treating AD. We initially found that the expression and production of VEGF was downregulated in the brains of Tg2576 mice during the course of AD development and progression. Restoring VEGF in the brains of Tg2576 mice antagonized the production and deposit of Aβ in Tg2576 mice...
April 24, 2018: Neuroscience Research
Yongli Xie, Qiong Liu, Lin Zheng, BingTao Wang, Xiaogang Qu, Jiazuan Ni, Yan Zhang, Xiubo Du
SCOPE: Se-methylselenocysteine (SMC) is a major selenocompound in selenium (Se) enriched plants such as garlic and broccoli florets. Se is vital for proper brain function, and Se-deficient is considered to be related with cognitive impairment and Alzheimer's disease (AD). In this study, we evaluated for the first time the potential of SMC in intervening cognitive deficits and neuropathology of triple transgenic AD (3 × Tg-AD) mice. METHODS AND RESULTS: AD mice were treated with SMC (0...
April 24, 2018: Molecular Nutrition & Food Research
Ting Yu, Pradeep Paudel, Su Hui Seong, Jeong Ah Kim, Hyun Ah Jung, Jae Sue Choi
The rhizome of Salvia miltiorrhiza has emerged as a rich source of natural therapeutic agents, and its several compounds are supposed to exhibit favorable effects on Alzheimer's disease (AD). The present work investigate the anti-AD potentials of 12 tanshinones, three salvianolic acids and three caffeic acid derivatives from S. miltiorrhiza via the inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Among the tested compounds, deoxyneocryptotanshinone (1), salvianolic acid A (13) and salvianolic acid C (15) displayed good inhibitory effect on BACE1 with IC50 values of 11...
April 13, 2018: Computational Biology and Chemistry
Pengzhen Wang, Xiaoyao Zheng, Qian Guo, Peng Yang, Xiaoying Pang, Kang Qian, Wei Lu, Qizhi Zhang, Xinguo Jiang
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme to cleave the amyloid precursor protein to develop Alzheimer's disease (AD). Reducing BACE1 expression in central neuron through RNA interference technology shows great promise to overcome AD. However, to obtain an efficient and neurons-specific delivery of siRNA against BACE1 through systemic administration remains challenging. Here, we design and prepare siRNA nano-carriers based on PEGylated poly(2-(N,N-dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) modified with both the CGN peptide for blood-brain barrier (BBB) penetration and the Tet1 peptide for neuron-specific binding...
April 18, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Jesus Campagna, Kanagasabai Vadivel, Barbara Jagodzinska, Michael Jun, Tina Bilousova, Patricia Spilman, Varghese John
The aspartyl protease BACE1 (BACE) has emerged as an appealing target for reduction of amyloid-β (Aβ) in Alzheimer's disease (AD). The clinical fate of active-site BACE inhibitors may depend on potential side effects related to enzyme- and substrate-selectivity. One strategy to reduce this risk is through development of allosteric inhibitors that interact with and modulate the Loop F region unique to BACE1. Previously, a BACE-inhibiting antibody (Ab) was shown by co-crystallization to bind and induce conformational changes of Loop F, resulting in backbone perturbations at the distal S6 and S7 subsites, preventing proper binding of a long APP-like substrate to BACE and inhibiting its cleavage...
April 9, 2018: Journal of Molecular Biology
Patrik Johansson, Karin Kaspersson, Ian K Gurrell, Elisabeth Back, Susanna Eketjäll, Clay W Scott, Gvido Cebers, Philip Thorne, Michael J McKenzie, Haydn Beaton, Paul Davey, Karin Kolmodin, Jorg Holenz, Mark E Duggan, Samantha Budd Haeberlein, Roland Werner Burli
BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aβ production and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Co-crystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles...
April 4, 2018: Journal of Medicinal Chemistry
Salvatore Bongarzone, Antony D Gee
No in vivo imaging biomarker currently exists for BACE, a drug target for Alzheimer's disease (AD). A strategy aiming to find a novel brain-penetrant positron emission tomography (PET) radiotracer for BACE1 led to the discovery of a highly potent and selective aminothiazine inhibitor, PF-06684511. This scaffold has been now evaluated as BACE1 PET radiotracer ([18 F]PF-06684511) after labeling with fluorine-18 (18 F), allowing its evaluation in non-human primates (NHP) as the first a brain-penetrant PET radiotracer for imaging BACE1 in vivo...
April 26, 2018: Journal of Medicinal Chemistry
Brian T O'Neill, Elizabeth M Beck, Christopher R Butler, Charles E Nolan, Cathleen Gonzales, Lei Zhang, Shawn D Doran, Kimberly Lapham, Leanne M Buzon, Jason K Dutra, Gabriela Barreiro, Xinjun Hou, Luis A Martinez-Alsina, Bruce N Rogers, Anabella Villalobos, John C Murray, Kevin Ogilvie, Erik A LaChapelle, Cheng Chang, Lorraine F Lanyon, Claire M Steppan, Ashley Robshaw, Katherine Hales, Germaine G Boucher, Karamjeet Pandher, Christopher Houle, Claude W Ambroise, David Karanian, David Riddell, Kelly R Bales, Michael A Brodney
A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically has only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype...
April 3, 2018: Journal of Medicinal Chemistry
Smriti Gupta, Kamalendra Yadav, Shrikant S Mantri, Nitin K Singhal, Subramaniam Ganesh, Rajat Sandhir
Evidence from animal studies categorizes sporadic Alzheimer's disease (sAD) as a metabolic syndrome with accompanying cognitive deficits. Given that glial cells act as "silent partners" to neurons by providing trophic support and defense, the present study investigated the role of glia in sAD pathology. A streptozotocin (STZ)-induced glial-neuronal co-culture model of sAD was used to study the metabolic status of the two cell types. Real time RT-PCR and Western blotting results indicated that amyloid precursor protein (APP) and β-secretase (BACE1) were highly expressed in co-cultured neurons than in monocultures...
April 3, 2018: Molecular Neurobiology
Paul J Meakin, Anna Mezzapesa, Eva Benabou, Mary E Haas, Bernadette Bonardo, Michel Grino, Jean-Michel Brunel, Christèle Desbois-Mouthon, Sudha B Biddinger, Roland Govers, Michael L J Ashford, Franck Peiretti
Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR...
April 3, 2018: Nature Communications
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