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Robert C Harris, Cheng-Chieh Tsai, Christopher R Ellis, Jana Shen
Many important pharmaceutical targets, such as aspartyl proteases and kinases, exhibit pH-dependent dynamics, functions and inhibition. Accurate prediction of their binding free energies is challenging because current computational techniques neglect the effects of pH. Here we combine free energy perturbation calculations with continuous constant pH molecular dynamics to explore the selectivity of a small-molecule inhibitor for β-secretase (BACE1), an important drug target for Alzheimer's disease. The calculations predicted identical affinity for BACE1 and the closely related cathepsin D at high pH; however, at pH 4...
September 21, 2017: Journal of Physical Chemistry Letters
Nadine Ruderisch, Daniel Schlatter, Andreas Kuglstatter, Wolfgang Guba, Sylwia Huber, Carlo Cusulin, Jörg Benz, Arne Christian Rufer, Joerg Hoernschemeyer, Christophe Schweitzer, Tina Bülau, Achim Gärtner, Eike Hoffmann, Jens Niewoehner, Christoph Patsch, Karlheinz Baumann, Hansruedi Loetscher, Eric Kitas, Per-Ola Freskgård
Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties...
September 7, 2017: EBioMedicine
Yuxiang Yuan, Zhiqi Chen, Lu Li, Xing Li, Qian Xia, Hong Zhang, Qiming Duan, Yin Zhao
Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. Previous MRI studies have revealed that POAG can be associated with alterations in hippocampal function. Thus, the aim of this study was to investigate a relationship between chronic high intraocular pressure (IOP) and hippocampal changes in a rat model. We used behavioural tests to assess learning and memory ability, and additionally investigated the hippocampal expression of pathological amyloid beta (Aβ), phospho-tau, and related pathway proteins...
September 8, 2017: Brain Research
Norsharina Ismail, Maznah Ismail, Nur Hanisah Azmi, Muhammad Firdaus Abu Bakar, Zhang Yida, Maizaton Atmadini Abdullah, Hamidon Basri
Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-β (Aβ) accumulation due to abnormal amyloid-β precursor protein (APP) processing and Aβ metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Aβ metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis...
September 8, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Yin-Hua Deng, Ning-Ning Wang, Zhen-Xing Zou, Lin Zhang, Kang-Ping Xu, Alex F Chen, Dong-Sheng Cao, Gui-Shan Tan
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder which is considered to be the most common cause of dementia. It has a greater impact not only on the learning and memory disturbances but also on social and economy. Currently, there are mainly single-target drugs for AD treatment but the complexity and multiple etiologies of AD make them difficult to obtain desirable therapeutic effects. Therefore, the choice of multi-target drugs will be a potential effective strategy inAD treatment...
2017: Frontiers in Pharmacology
Rongfeng Liu, Yu-Chih Liu, Junwei Meng, Haiyan Zhu, Xuehong Zhang
The β-secretase (BACE1) initiates the generation of toxic amyloid-β peptide (Aβ) from amyloid-β precursor protein (APP), which was widely considered to play a key role in the pathogenesis of Alzheimer's disease (AD). Here, a novel microfluidics-based mobility shift assay (MMSA) was developed, validated, and applied for the screening of BACE1 inhibitors for AD. First, the BACE1 activity assay was established with a new fluorescent peptide substrate (FAM-EVNLDAEF) derived from the Swedish mutant APP, and high-quality ratiometric data were generated in both endpoint and kinetic modes by electrophoretic separation of peptide substrate from the BACE1 cleaved product (FAM-EVNL) before fluorescence quantification...
September 9, 2017: Analytical and Bioanalytical Chemistry
Xiang-Sheng Cai, Zhao-Guang Tan, Jing-Jing Li, Wei-Hong Gao, Shu-Ji Li, Jin-Long Li, Yong-Ming Tang, Hong-Wei Li, Hong-Xiang Hui
BACKGROUND Glucagon-like peptide-1 (GLP-1) has been reported to exert some beneficial effects on the central nervous system (CNS). However, the effect of GLP-1 on cognitive impairment associated with type 2 diabetes is not well known. This study investigated the effect of GLP-1 on ameliorating memory deficits in type 2 diabetic rats. MATERIAL AND METHODS Type 2 diabetic rats were induced by a high-sugar, high-fat diet, followed by streptozotocin (STZ) injection and then tested in the Morris Water Maze (MWM) 1 week after the induction of diabetes...
September 8, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Khalil Saadipour, Noralyn B Mañucat-Tan, Yoon Lim, Damien J Keating, Kevin S Smith, Jin-Hua Zhong, Hong Liao, Larisa Bobrovskaya, Yan-Jiang Wang, Moses V Chao, Xin-Fu Zhou
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid-beta (Aβ) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aβ...
September 4, 2017: Journal of Neurochemistry
Kumju Youn, Yoonjin Yu, Jinhyuk Lee, Woo-Sik Jeong, Chi-Tang Ho, Mira Jun
Beta-site amyloid precursor protein (APP) cleaving enzyme1 (BACE1) catalyzes the rate-limiting step of amyloid-β protein (Aβ) generation, and is considered as a prime target for Alzheimer's disease (AD). In search of a candidate for AD prevention, our efforts exploring the natural BACE1 inhibitor have led to the finding of nobiletin, tangeretin, and sinensetin-representative compounds of polymethoxyflavones (PMFs). Tangeretin exhibited the strongest BACE1 inhibition (IC50, 4.9 × 10(-5) M), followed by nobiletin and sinensetin with IC50 values of 5...
September 4, 2017: Nutrients
Aparna Chaudhary, Sanjeev Garg
Small interfering RNA (siRNA) mediated RNA interference is a versatile therapeutic tool for many intractable genetic disorders. Various nanoassemblies specifically designed to deliver the siRNAs could be utilized for efficient siRNA delivery which is one of the major concern for the success of this therapeutic. Thus, in the present study, polyelectrolyte-gold nanoassemblies (PE-Gold NAs) were selected for siRNA delivery of an in vitro verified siRNA. Three different polyelectrolytes (polyethyleneimine, citraconic anhydride modified poly (allylamine) hydrochloride and poly l-arginine) were used to formulate the PE-Gold NAs using the layer-by-layer technique...
November 1, 2017: Materials Science & Engineering. C, Materials for Biological Applications
Madhurima Chatterjee, Bernd Nöding, Eline A J Willemse, Marleen J A Koel-Simmelink, Wiesje M van der Flier, Detlev Schild, Charlotte E Teunissen
OBJECTIVES: Alzheimer's disease (AD) is the most common cause of dementia in the world. As many AD biomarkers occur at rather low abundances in CSF or blood, techniques of very high sensitivity and accuracy are important as diagnostic tools in the clinic. Here, we aimed to provide proof of concept of the use of a single molecule detection technique, Fluorescence Correlation Spectroscopy (FCS) for detection of novel candidate biomarkers for AD. DESIGN AND METHODS: FCS detects the diffusion times of the antigen-antibody complexes in highly diluted sample solutions, thus eliminating the need of large sample volumes and allows estimating the concentration of the target antigen...
August 28, 2017: Clinical Biochemistry
Daniela Bumbaca Yadav, Janice A Maloney, Kristin R Wildsmith, Reina N Fuji, William J Meilandt, Hilda Solanoy, Yanmei Lu, Kun Peng, Blair Wilson, Pamela Chan, Kapil Gadkar, Andrew Kosky, Marisa Goo, Ann Daugherty, Jessica A Couch, Thomas Keene, Karen Hayes, Lisa Jungbauer Nikolas, Deanna Lane, Robert Switzer, Eric Adams, Ryan J Watts, Kimberly Scearce-Levie, Saileta Prabhu, Lisa Shafer, Deepak R Thakker, Keith Hildebrand, Jasvinder K Atwal
BACKGROUND AND PURPOSE: The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. Intracerebroventricular (i.c.v.) delivery is a promising route to the brain, however it is unclear how efficiently i.c.v - delivered antibodies penetrate the cerebrospinal fluid (CSF)-brain barrier and distribute throughout the brain parenchyma. EXPERIMENTAL APPROACH: We evaluated the pharmacokinetics and pharmacodynamics of an inhibitory monoclonal antibody against β-site amyloid precursor protein cleaving enzyme 1 (anti-BACE1) following continuous infusion into the left lateral ventricle of healthy adult cynomolgus monkeys...
August 31, 2017: British Journal of Pharmacology
Brati Das, Riqiang Yan
Alzheimer's disease (AD) is the most common age-dependent disease of dementia, and there is currently no cure available. This hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary tangles. Although the exact etiology of AD remains a mystery, studies over the past 30 have shown that abnormal generation or accumulation of β-amyloid peptides (Aβ) is likely to be a predominant early event in AD pathological development. Aβ is generated from amyloid precursor protein (APP) via proteolytic cleavage by β-site APP cleaving enzyme 1 (BACE1)...
2017: Translational Neurodegeneration
Gee Euhn Choi, Sei-Jung Lee, Hyun Jik Lee, So Hee Ko, Chang Woo Chae, Ho Jae Han
Glucocorticoid has been widely accepted to induce Alzheimer's disease, but the nongenomic effect of glucocorticoid on amyloid β (Aβ) generation has yet to be studied. Here, we investigated the effect of the nongenomic pathway induced by glucocorticoid on amyloid precursor protein processing enzymes as well as Aβ production using male ICR mice and human neuroblastoma SK-N-MC cells. Mice groups exposed to restraint stress or intracerebroventricular injection of Aβ showed impaired cognition, decreased intracellular glucocorticoid receptor (GR) level, but elevated level of membrane GR (mGR)...
August 30, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Tingting Ku, Ben Li, Rui Gao, Yingying Zhang, Wei Yan, Xiaotong Ji, Guangke Li, Nan Sang
BACKGROUND: PM2.5 (particulate matter ≤ 2.5 μm) is one of the leading environmental risk factors for the global burden of disease. Whereas increasing evidence has linked the adverse roles of PM2.5 with cardiovascular and respiratory diseases, limited but growing emerging evidence suggests that PM2.5 exposure can affect the nervous system, causing neuroinflammation, synaptic dysfunction and cognitive deterioration. However, the molecular mechanisms underlying the synaptic and cognitive deficits elicited by PM2...
August 29, 2017: Particle and Fibre Toxicology
Jian-Ming Li, Li-Ling Huang, Fei Liu, Bei-Sha Tang, Xiao-Xin Yan
BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of ß-amyloid peptides (Aß) in and surrounding the wall of microvasculature in the central nervous system, together with parenchymal amyloid plaques collectively referred to as cerebral amyloidosis, which occurs in the brain commonly among the elderly and more frequently in patients with Alzheimer's disease (AD). CAA is associated with vascular injury and may cause devastating neurological outcomes. No therapeutic approach is available for this lesion to date...
August 25, 2017: BMC Neurology
Zhiyou Cai, Zhou Liu, Ming Xiao, Chuanling Wang, Fuming Tian
Chronic cerebral hypoperfusion (CCH) contributes to the Alzheimer's-like pathogenesis, but the relationship between CCH and the occurrence of Alzheimer's disease (AD) remains obscure. The aim is to elucidate the potential pathophysiological mechanism in the field of amyloid-beta (Aβ) pathology induced by CCH. A rat model of CCH has been developed with permanent bilateral occlusion of common carotid arteries (BCCAO). The cognitive function of rats was tested by the Morris water maze. The levels of Aβ (Aβ40 and Aβ42) and soluble amyloid precursor protein (sAPP: sAPPα and sAPPβ) were determined by enzyme linked immunosorbent assay...
August 24, 2017: Neurochemical Research
Haijing Zhang, Chunhui Zhao, Guoqiong Cao, Limin Guo, Shuai Zhang, Yuexia Liang, Chunxia Qin, Ping Su, Hang Li, Wensheng Zhang
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by memory deficits and cognitive decline. Excessive amyloid-β (Aβ) peptide aggregates and forms soluble oligomers and insoluble cerebral amyloid plaques, which is widely thought to be the underlying pathogenic mechanism of AD. Therefore, effective regulation of Aβ metabolism is an important aspect of preventing and improving AD. Berberine, which is the main active component of the traditional medicinal herb Coptidis rhizoma, has a positive effect on reducing Aβ levels...
August 16, 2017: Neuropharmacology
Charbel E-H Moussa
BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-β peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Aβ accumulation and halt AD onset and progression...
October 2017: Expert Opinion on Investigational Drugs
Rebecca Ek MacPherson
Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer's disease (AD). Several studies have demonstrated that diet induced obesity, inactivity, and insulin resistance exacerbates neuropathological hallmarks of AD. The aggregation of beta-amyloid peptides is one of these hallmarks. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to beta-amyloid peptide formation...
August 16, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
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