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Eline T S van Maanen, Tamara S van Steeg, Maurice Ahsman, Maria S Michener, Mary J Savage, Matthew E Kennedy, Huub J Kleijn, Julie A Stone, Meindert Danhof
The abnormal accumulation of amyloid-β (Aβ) in the brain parenchyma has been posited as a central event in the pathophysiology of Alzheimer's disease. Recently, we have proposed a systems pharmacology model of the APP pathway, describing the Aβ precursor protein (APP) metabolite responses (Aβ40, Aβ42, sAPPα and sAPPβ) to β-secretase 1 (BACE1) inhibition (van Maanen et al., 2016). In this investigation this model was challenged to describe Aβ dynamics following γ-secretase (GS) inhibition. This led an extended systems pharmacology model, with separate descriptions to characterize the sequential cleavage steps of APP by BACE1 and GS, to describe the differences in Aβ response to their respective inhibition...
March 21, 2018: Journal of Pharmacology and Experimental Therapeutics
Ahsan Habib, Huayan Hou, Takashi Mori, Jun Tian, Jin Zeng, Shengnuo Fan, Brian Giunta, Paul R Sanberg, Darrell Sawmiller, Jun Tan
Alzheimer's disease (AD) is an age-related disorder that affects cognition. Our previous studies showed that the neuroprotective fragment of amyloid procurer protein (APP) metabolite, soluble APPα (sAPPα), interferes with β-site APP-cleaving enzyme 1 (BACE1, β-secretase) cleavage and reduces amyloid-β (Aβ) generation. In an attempt to identify approaches to restore sAPPα levels, we found that human cord blood serum (CBS) significantly promotes sAPPα production compared with adult blood serum (ABS) and aged blood serum (AgBS) in Chinese hamster ovary cells stably expressing wild-type human APP...
January 1, 2018: Cell Transplantation
Yongming Pan, Jianqin Xu, Cheng Chen, Fangming Chen, Ping Jin, Keyan Zhu, Chenyue W Hu, Mengmeng You, Minli Chen, Fuliang Hu
Alzheimer's disease (AD) is the most common form of dementia characterized by aggregation of amyloid β (Aβ) and neuronal loss. One of the risk factors for AD is high cholesterol levels, which are known to promote Aβ deposition. Previous studies have shown that royal jelly (RJ), a product of worker bees, has potential neuroprotective effects and can attenuate Aβ toxicity. However, little is known about how RJ regulates Aβ formation and its effects on cholesterol levels and neuronal metabolic activities...
2018: Frontiers in Aging Neuroscience
Yong-Zhe Zhu, Jing-Wen Liu, Xue Wang, In-Hong Jeong, Young-Joon Ahn, Chuan-Jie Zhang
The human β-site amyloid cleaving enzyme (BACE1) has been considered as an effective drug target for treatment of Alzheimer's disease (AD). In this study, Urechis unicinctus (U. unicinctus) , which is a Far East specialty food known as innkeeper worm, ethanol extract was studied by bioassay-directed fractionation and isolation to examine its potential β-site amyloid cleaving enzyme inhibitory and antimicrobial activity. The following compounds were characterized: hecogenin, cholest-4- en -3-one, cholesta-4,6- dien -3-ol, and hurgadacin...
March 14, 2018: Marine Drugs
Aditi Wagle, Su Hui Seong, Bing Tian Zhao, Mi Hee Woo, Hyun Ah Jung, Jae Sue Choi
Hizikia fusiformis (Harvey) Okamura is a brown seaweed widely used in Korea and Japan, and it contains different therapeutically active constituents. In the present study, we investigated the activities of glycyrrhizin isolated from H. fusiformis, including its metabolites, 18α- and 18β-glycyrrhetinic acid against Alzheimer's disease (AD) via acetyl and butyrylcholinesterase and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition. Among these three compounds, 18β-glycyrrhetinic acid (IC50  = 8...
March 12, 2018: Archives of Pharmacal Research
Gaia Botteri, Laia Salvadó, Anna Gumà, D Lee Hamilton, Paul J Meakin, Gemma Montagut, Michael L J Ashford, Victoria Ceperuelo-Mallafré, Sonia Fernández-Veledo, Joan Vendrell, María Calderón-Dominguez, Dolors Serra, Laura Herrero, Javier Pizarro, Emma Barroso, Xavier Palomer, Manuel Vázquez-Carrera
OBJECTIVE: β-secretase/β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a key enzyme involved in Alzheimer's disease that has recently been implicated in insulin-independent glucose uptake in myotubes. However, it is presently unknown whether BACE1 and the product of its activity, soluble APPβ (sAPPβ), contribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells. MATERIALS/METHODS: Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1-/- mice and mice treated with sAPPβ and adipose tissue and plasma from obese and type 2 diabetic patients...
March 8, 2018: Metabolism: Clinical and Experimental
Ru-Yi Zhang, Lan Zhang, Li Zhang, Yu-Lan Wang, Lin Li
Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. Emerging evidence indicates that there is a tight relationship between mitochondrial dysfunction and β-amyloid (Aβ) formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on Aβ production and neurotrophins in the brains of rats by using a mitochondrial dysfunction rat model induced by sodium azide (NaN3 ), an inhibitor of mitochondrial cytochrome c oxidase (COX)...
March 5, 2018: Journal of Natural Medicines
Stephanie Hartmann, Fang Zheng, Michele Constanze Kyncl, Sandra Karch, Kerstin Voelkl, Benedikt Zott, Carla D'Avanzo, Selene Lomoio, Giuseppina Tesco, Doo Yeon Kim, Christian Alzheimer, Tobias Huth
β-Secretase BACE1 is deemed a major culprit in Alzheimer's disease, but accumulating evidence indicates that there is more to the enzyme than driving the amyloidogenic processing of the amyloid precursor protein. For example, BACE1 has emerged as an important regulator of neuronal activity through proteolytic and, most unexpectedly, also through non-proteolytic interactions with several ion channels. Here, we identify and characterize the voltage-gated K+ channel 3.4 as a new and functionally relevant interaction partner of BACE1...
March 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Nafiseh Nafisi-Far, Soudeh Ghafouri-Fard, Akram Sadat Tabatabaei Panah, Arezou Sayad, Mohammad Taheri
Schizophrenia has long been considered as a devastating brain disorder in which both genetic and environmental factors are involved. The BACE1 gene is one of the most important susceptibility genes for this disorder. However, the changes in BACE1 expression in schizophrenic patients compared with healthy subjects have not been evaluated yet. In this case-control study, we examined BACE1 expression in a group of 50 patients with schizophrenia and 50 healthy controls. The level of BACE1 gene expression was measured using Real-Time PCR...
March 3, 2018: Metabolic Brain Disease
Eun-Jeong Koh, Kui-Jin Kim, Jia Choi, Do-Hyung Kang, Boo-Yong Lee
Spirulina maxima is a blue-green micro alga that contains abundant amounts of proteins (60-70%), vitamins, chlorophyll a, and C-phycocyanin (C-PC). It has been shown to reduce oxidative stress, and prevent diabetes and non-alcoholic fatty liver disease. However, it is unclear whether Spirulina maxima 70% ethanol extract (SM70EE), chlorophyll a, and C-PC prevent Aβ1-42 -induced neurotoxicity in PC12 cells. The aim of this study was to investigate whether SM70EE, chlorophyll a, and C-PC prevent Aβ1-42 -induced cell death...
February 27, 2018: Neuroscience Letters
Sylvie L Lesuis, Sascha Weggen, Sandra Baches, Paul J Lucassen, Harm J Krugers
Exposure to chronic stress or elevated glucocorticoid hormone levels in adult life has been associated with cognitive deficits and an increased risk for Alzheimer's disease (AD). Since exposure to stress during early life enhances stress-responsiveness and lastingly affects cognition in adult life, we here investigated; (i) whether chronic early life stress (ELS) affects AD pathology and cognition in middle-aged APPswe/PS1dE9 mice, and (ii) whether it is still possible to rescue these late effects by briefly blocking glucocorticoid receptors (GRs) at a translationally relevant, middle age...
March 1, 2018: Translational Psychiatry
Zeng Li, Xiao-Chang Liu, Rui Li, Jun Chang
BACKGROUND Beta-secretase 1 (BACE1) is a rate-limiting enzyme in the generation of amyloid beta peptides, which are associated with Alzheimer's disease (AD). It has been reported that Schisandrin B could improve cognitive functions in animal models of AD, but the underlying mechanisms are not completely understood. MATERIAL AND METHODS In this research, in order to investigate the effects of Schisandrin B on amyloid-β (Aβ) metabolism and its mechanisms, amyloid precursor protein (APP) and its proteolytic products were determined by enzyme-linked immunosorbent assay (ELISA), western blotting, and RT-PCR after incubation of N2a/Swe cells with Schisandrin B...
February 28, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Chi Zhang, Zhichun Gu, Long Shen, Xianyan Liu, Houwen Lin
BACKGROUND: Alzheimer's disease (AD) is one of most serious threat for human beings, however, the treatment was hindered by blood brain barrier and poor intra-brain cell selectivity. METHODS: In this study, we developed a novel dual targeting drug delivery system by modification NL4 peptide and apolipoprotein A-I (ApoA-I) onto dendrimer particles that may efficiently deliver siRNA into neuron cells to down-regulate BACE1 and inhibit Aβ formation. The constructed ANNP/siRNA was approximately 79...
February 26, 2018: Current Pharmaceutical Biotechnology
David A Thaisrivongs, William J Morris, Lushi Tan, Zhiguo J Song, Thomas W Lyons, Jacob H Waldman, John R Naber, Wenyong Chen, Lu Chen, Baoyun Zhang, Jun Yang
The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.
February 26, 2018: Organic Letters
Mohammad H Baig, Khurshid Ahmad, Gulam Rabbani, Inho Choi
Alzheimer's disease (AD) is a form of dementia and the most common progressive neurodegenerative disease (ND). The targeting of amyloid-beta (Aβ) aggregation is one of the most widely used strategies to manage AD, and efforts are being made globally to develop peptide-based compounds for the early diagnosis and treatment of AD. Here, we briefly discuss the use of peptide-based compounds for the early diagnosis and treatment of AD and the use of peptide-based inhibitors targeting various Aβ aggregation checkpoints...
2018: Frontiers in Aging Neuroscience
Raphael Hesse, Björn von Einem, Franziska Wagner, Patricia Bott, Daniel Schwanzar, Rosemary J Jackson, Karl Josef Föhr, Ludwig Lausser, Katja S Kroker, Christian Proepper, Paul Walther, Hans A Kestler, Tara L Spires-Jones, Tobias Boeckers, Holger Rosenbrock, Christine A F von Arnim
One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid β (Aβ). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aβ production and soluble APPβ (sAPPβ) levels. Aβ is known to impair synaptic function; however, much less is known about the physiological functions of sAPPβ. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPβ exist...
February 18, 2018: Experimental Neurology
Jia Wang, Lixia Li, Zhuo Wang, Yifan Cui, Xintong Tan, Tian Yuan, Qian Liu, Zhigang Liu, Xuebo Liu
Neuroinflammation is documented to be the major culprit of Alzheimer's disease. Lycopene (LYC), a fat soluble carotenoid, exhibits neuroprotective function in several neurodegenerative disorders. However, the effects of LYC to countering systemic inflammation-induced amyloidogenesis and memory deficiency remain to be elucidated. In current study, 3-month-old male C57BL/6J mice were treated with 0.03% LYC (w/w, mixed into normal chow) for 5 weeks. The mice were then treated by intraperitoneal injection of LPS (0...
February 2, 2018: Journal of Nutritional Biochemistry
Xiangyou Hu, Brati Das, Hailong Hou, Wanxia He, Riqiang Yan
BACE1 initiates the generation of the β-amyloid peptide, which likely causes Alzheimer's disease (AD) when accumulated abnormally. BACE1 inhibitory drugs are currently being developed to treat AD patients. To mimic BACE1 inhibition in adults, we generated BACE1 conditional knockout (BACE1 fl/fl ) mice and bred BACE1 fl/fl mice with ubiquitin-Cre ER mice to induce deletion of BACE1 after passing early developmental stages. Strikingly, sequential and increased deletion of BACE1 in an adult AD mouse model (5xFAD) was capable of completely reversing amyloid deposition...
February 14, 2018: Journal of Experimental Medicine
Kumju Youn, Ji-Hyun Park, Seonah Lee, Seungeun Lee, Jinhyuk Lee, Eun-Young Yun, Woo-Sik Jeong, Mira Jun
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a role in generating amyloid β (Aβ), thus playing a major part early in the pathogenesis of Alzheimer's disease (AD). BACE1 has emerged as a crucial therapeutic target for decreasing the Aβ concentration in the AD brain. To explore natural BACE1 inhibitors, the present study concentrated on isoflavones, including genistein, formononetin, glycitein, daidzein, and puerarin. In this study, in vitro anti-AD activities were assessed using BACE1 inhibition assays, as well as enzyme kinetic predictions...
February 14, 2018: Journal of Medicinal Food
Michael D Ehlers
No abstract text is available yet for this article.
March 1, 2018: Biological Psychiatry
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