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https://www.readbyqxmd.com/read/28432138/inhibition-of-drp1-ameliorates-synaptic-depression-a%C3%AE-deposition-and-cognitive-impairment-in-alzheimer-s-disease-model
#1
Seung-Hyun Baek, So Jung Park, Jae In Jeong, Sung Hyun Kim, Jihoon Han, Jae Won Kyung, Sang-Ha Baik, Yuri Choi, Bo-Youn Choi, Jinsu Park, Gahee Bahn, Ji Hyun Shin, Doo Sin Jo, Joo-Yong Lee, Choon-Gon Jang, Thiruma V Arumugam, Jongpil Kim, Jeung-Whan Han, Jae-Young Koh, Dong-Hyung Cho, Dong-Gyu Jo
Excessive mitochondrial fission is a prominent early event, and contributes to mitochondrial dysfunction, synaptic failure and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examine the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric β-amyloid (Aβ) in neurons, and neuropathology and cognitive functions in APP/PS1 double transgenic AD mice...
April 21, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28427814/design-synthesis-and-x-ray-structural-studies-of-bace-1-inhibitors-containing-substituted-2-oxopiperazines-as-p1-p2-ligands
#2
Arun K Ghosh, Margherita Brindisi, Yu-Chen Yen, Emilio L Cárdenas, Jean-Rene Ella-Menye, Nagaswamy Kumaragurubaran, Xiangping Huang, Jordan Tang, Andrew D Mesecar
We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1' and P2' ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki=2nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated...
April 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28413992/screening-and-elucidation-of-selected-natural-compounds-for-anti-alzheimer-s-potential-targeting-bace-1-enzyme-a-case-computational-study
#3
Syed Sayeed Ahmad, Salman Akhtar, Syed Mohd Danish Rizvi, Mohammad A Kamal, Usman Sayeed, Mohd Kalim A Khan, Mohd Haris Siddiqui, Jamal M Arif
BACKGROUND: The present study clarifies the molecular interactions of human BACE1 with novel natural ligands and also with the well-known ligand 2, 2, 4-trihydroxychalcone and Galangin for comparison. OBJECTIVE: The study of enzyme- ligands interaction is interest, description of ligands binding to the active site of target molecule could be beneficial to better understanding the mechanism of the ligand on the target molecule. METHOD: Lipinski rule of five, and docking study was performed between ligands and enzyme using 'Autodock4...
April 14, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28413985/salvianolic-acid-b-decreases-the-generation-of-amyloid-%C3%AE-by-modulating-bace1-activity
#4
Siva Sundara Kumar Durairajan, Venkat Reddy Chirasani, Sravan Gopalakrishnan Shetty, Ashok Iyaswamy, Sandeep Malampati, Juxian Song, Liangfeng Liu, Jiandong Huang, Sanjib Senapati, Min Li
Generation and accumulation of the amyloid-β (Aβ) peptide after proteolytic processing of the full length amyloid precursor protein (FL-APP) by β-secretase (β-site APP cleaving enzyme or BACE1) and β -secretase is a main causal factor of Alzheimer's disease (AD). Thus, inhibition of BACE1, a rate-limiting enzyme in the production of Aβ, is an attractive therapeutic approach for the treatment of AD. Recent studies suggest that salvianolic acid B (Sal B) isolated from the radix of Salvia miltiorrhiza Bunge, a Chinese herbal medicine commonly used for the treatment of cardiovascular, cerebrovascular and liver diseases in China...
April 17, 2017: Current Alzheimer Research
https://www.readbyqxmd.com/read/28413720/direct-imaging-of-app-proteolysis-in-living-cells
#5
Niccoló Parenti, Ambra Del Grosso, Claudia Antoni, Marco Cecchini, Renato Corradetti, Francesco S Pavone, Martino Calamai
Alzheimer's disease is a multifactorial disorder caused by the interaction of genetic, epigenetic and environmental factors. The formation of cytotoxic oligomers consisting of Aβ peptide is widely accepted as being one of the main key events triggering the development of Alzheimer's disease. Aβ peptide production results from the specific proteolytic processing of the amyloid precursor protein (APP). Deciphering the factors governing the activity of the secretases responsible for the cleavage of APP is still a critical issue...
2017: PeerJ
https://www.readbyqxmd.com/read/28409157/ferulic-acid-suppresses-amyloid-%C3%AE-production-in-the-human-lens-epithelial-cell-stimulated-with-hydrogen-peroxide
#6
Noriaki Nagai, Sachiyo Kotani, Yu Mano, Akina Ueno, Yoshimasa Ito, Toshio Kitaba, Takumi Takata, Noriko Fujii
It is well known that oxidative stresses induce the production of amyloid β (Aβ) in the brain, lens, and retina, leading to age-related diseases. In the present study, we investigated the effects of ferulic acid on the Aβ levels in H2O2-stimulated human lens epithelial (HLE) SRA 01/04 cells. Three types of Aβ peptides (Aβ1-40, Aβ1-42, and Aβ1-43) were measured by ELISA, and the levels of mRNA for the expressed proteins related to Aβ production (APP, BACE1, and PS proteins) and degradation (ADAM10, NEP, and ECE1 proteins) were determined by quantitative real-time RT-PCR...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28384043/association-of-%C3%AE-secretase-functional-polymorphism-with-risk-of-schizophrenia
#7
Simin Rahimi-Aliabadi, Neda Shahmohammadibeni, Javad Jamshidi, Ehsan Esmaili Shandiz, Reza Mirfakhraie, Mina Ohadi, Farhad Ramezani Nejad, Nader Mansoori, Mohammad Taheri, Fatemeh Gholipour, Susan Moudi, Gouya Tayebi, Shahram Divsalar, Hossein Darvish, Abolfazl Movafagh
AIM: The NRG1-ERBB4 neurotransmitter signaling pathway plays a key role in the pathogenesis of schizophrenia (SZ). The intronic single-nucleotide polymorphism rs707284 in ERBB4 links to PI3K-AKT suppression in SZ. Another protein indirectly affecting NRG1-ERBB4 signaling is β-secretase, which is encoded by the BACE1 gene, and activates NRG1 by proteolytic cleavage. In this study, we aimed to investigate the association of ERBB4 rs707284 and BACE1 rs490460 with the risk of SZ in an Iranian population...
April 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28382744/exercise-and-bdnf-reduce-a%C3%AE-production-by-enhancing-%C3%AE-secretase-processing-of-app
#8
Saket M Nigam, Shaohua Xu, Joanna S Kritikou, Krisztina Marosi, Lennart Brodin, Mark P Mattson
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by aggregation of toxic forms of amyloid β peptide (Aβ). Treatment strategies have largely been focused on inhibiting the enzymes (β- and γ-secretases) that liberate Aβ from the amyloid precursor protein (APP). While evidence suggests that individuals who exercise regularly are at reduced risk for AD and studies of animal models demonstrate that running can ameliorate brain Aβ pathology and associated cognitive deficits, the underlying mechanisms are unknown...
April 6, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28381772/inhibition-of-%C3%AE-secretase-activity-by-monoterpenes-sesquiterpenes-and-c13-norisoprenoids
#9
Shinsuke Marumoto, Yoshiharu Okuno, Mitsuo Miyazawa
Inhibition of β-secretase (BACE1) is currently regarded as the leading treatment strategy for Alzheimer's disease. In the present study, we aimed to screen the in vitro inhibitory activity of 80 types of aroma compounds (monoterpenes, sesquiterpenes, and C13 norisoprenoids), including plant-based types, at a 200-μM concentration against a recombinant human BACE1. The results showed that the most potent inhibitor of BACE1 was geranyl acetone followed by (+)-camphor, (-)-fenchone, (+)-fenchone, and (-)-camphor with the half-maximal inhibitory concentration (IC50) values of 51...
April 4, 2017: Journal of Oleo Science
https://www.readbyqxmd.com/read/28371615/mechanisms-that-synergistically-regulate-%C3%AE-secretase-processing-of-app-and-a%C3%AE-%C3%AE-protein-levels-relevance-to-pathogenesis-and-treatment-of-alzheimer-s-disease
#10
Joseph Ward, Haizhi Wang, Aleister J Saunders, Rudolph E Tanzi, Can Zhang
The pathophysiology of Alzheimer's disease (AD) is characterized by the formation of cerebral β-amyloid plaque from a small peptide amyloid-β (Aβ). Aβ is generated from the canonical amyloid-β precursor protein (APP) proteolysis pathway through β- and γ-secretases. Decreasing Aβ levels through targeting APP processing is a very promising direction in clinical trials for AD. A novel APP processing pathway was recently identified, in which η-secretase processing of APP occurs and results in the generation of the carboxy-terminal fragment-η (CTF-η or η-CTF) (Wang et al...
February 2017: Discovery Medicine
https://www.readbyqxmd.com/read/28370344/conformational-dynamics-of-cathepsin-d-and-binding-to-a-small-molecule-bace1-inhibitor
#11
Christopher R Ellis, Cheng-Chieh Tsai, Fang-Yu Lin, Jana Shen
BACE1 is a major therapeutic target for prevention and treatment of Alzheimer's disease. Developing inhibitors that can selectively target BACE1 in favor of other proteases, especially cathepsin D (CatD), has presented significant challenges. Here, we investigate the conformational dynamics and protonation states of BACE1 and CatD using continuous constant pH molecular dynamics with pH replica-exchange sampling protocol. Despite similar structure, BACE1 and CatD exhibit markedly different active site dynamics...
April 2, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28359674/design-and-synthesis-of-bicyclic-acetals-as-beta-secretase-bace1-inhibitors
#12
Riccardo Innocenti, Elena Lenci, Gloria Menchi, Alberto Pupi, Andrea Trabocchi
Taking advantage of the structural similarity between aspartic proteases, small-molecule peptidomimetic inhibitors that already showed activity towards Secreted Aspartic Protease 2 as anti-Candida agents and HIV protease inhibitors were exploited as potential BACE1 inhibitors. A focused library of 6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetic scaffolds was synthesized and assayed towards BACE1 enzyme, resulting in the identification of a thiolactam-containing hit compound possessing IC50 in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues...
March 18, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28359566/increased-plasma-beta-secretase-1-may-predict-conversion-to-alzheimer-s-disease-dementia-in-individuals-with-mild-cognitive-impairment
#13
Yong Shen, Haibo Wang, Qiying Sun, Hailan Yao, Andrew P Keegan, Mike Mullan, Jeffrey Wilson, Simone Lista, Thomas Leyhe, Christoph Laske, Dan Rujescu, Allan Levey, Anders Wallin, Kaj Blennow, Rena Li, Harald Hampel
BACKGROUND: Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects...
March 27, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28355692/-influence-of-aluminum-on-microrna29-and-%C3%AE-site-amyloid-precursor-protein-cleaving-enzyme-1-in-the-brain-of-rats
#14
L P Wang, J L Hu, Y Zhao, L Zhang, Q Niu
Objective: To investigate the influence of aluminum on microRNA29 (miR29) subtypes miR29a, miR29a*, miR29b1, miR29b2, miR29c1, and miR29c2 and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in the brain of rats. Methods: A total of 40 Sprague-Dawley rats were randomly divided into control group and 15, 30, and 45 μmol/kg groups according to the body weight, with 10 rats in each group. The rats were exposed to aluminum (at a dose of 0.1 ml/100 g body weight) by intraperitoneal injection for 8 weeks...
February 20, 2017: Chinese Journal of Industrial Hygiene and Occupational Diseases
https://www.readbyqxmd.com/read/28337142/icariside-ii-effectively-reduces-spatial-learning-and-memory-impairments-in-alzheimer-s-disease-model-mice-targeting-beta-amyloid-production
#15
Lingli Yan, Yuanyuan Deng, Jianmei Gao, Yuangui Liu, Fei Li, Jingshan Shi, Qihai Gong
Icariside II (ICS II) is a broad-spectrum anti-cancer natural compound extracted from Herba Epimedii Maxim. Recently, the role of ICS II has been investigated in central nervous system, especially have a neuroprotective effect in Alzheimer's disease (AD). In this study, we attempted to investigate the effects of ICS II, on cognitive deficits and beta-amyloid (Aβ) production in APPswe/PS1dE9 (APP/PS1) double transgenic mice. It was found that chronic ICS II administrated not only effectively ameliorated cognitive function deficits, but also inhibited neuronal degeneration and reduced the formation of plaque burden...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28334857/co-cultures-with-stem-cell-derived-human-sensory-neurons-reveal-regulators-of-peripheral-myelination
#16
Alex J Clark, Malte S Kaller, Jorge Galino, Hugh J Willison, Simon Rinaldi, David L H Bennett
See Saporta and Shy (doi:10.1093/awx048) for a scientific commentary on this article.Effective bidirectional signalling between axons and Schwann cells is essential for both the development and maintenance of peripheral nerve function. We have established conditions by which human induced pluripotent stem cell-derived sensory neurons can be cultured with rat Schwann cells, and have produced for the first time long-term and stable myelinating co-cultures with human neurons. These cultures contain the specialized domains formed by axonal interaction with myelinating Schwann cells, such as clustered voltage-gated sodium channels at the node of Ranvier and Shaker-type potassium channel (Kv1...
April 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28315680/selenoprotein-s-is-required-for-clearance-of-c99-through-endoplasmic-reticulum-associated-degradation
#17
Jun Ki Jang, Ki Jun Park, Jea Hwang Lee, Kwan Young Ko, Seongman Kang, Ick Young Kim
Amyloid beta precursor protein (APP) is normally cleaved by α-secretase, but can also be cleaved by β-secretase (BACE1) to produce C99 fragments in the endoplasmic reticulum (ER) membrane. C99 is subsequently cleaved to amyloid β (Aβ), the aggregation of which is known to cause Alzheimer's disease. Therefore, C99 removing is for preventing the disease. Selenoprotein S (SelS) is an ER membrane protein participating in endoplasmic reticulum-associated degradation (ERAD), one of the stages in resolving ER stress of misfolded proteins accumulated in the ER...
March 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28304295/palmitate-increases-%C3%AE-site-a%C3%AE-pp-cleavage-enzyme-1-activity-and-amyloid-%C3%AE-genesis-by-evoking-endoplasmic-reticulum-stress-and-subsequent-c-ebp-homologous-protein-activation
#18
Gurdeep Marwarha, Stephen Rostad, Jaclyn Lilek, Mason Kleinjan, Jared Schommer, Othman Ghribi
Epidemiological studies implicate diets rich in saturated free fatty acids (sFFA) as a potential risk factor for developing Alzheimer's disease (AD). In particular, high plasma levels of the sFFA palmitic acid (palmitate) were shown to inversely correlate with cognitive function. However, the cellular mechanisms by which sFFA may increase the risk for AD are not well known. Endoplasmic reticulum (ER) stress has emerged as one of the signaling pathways initiating and fostering the neurodegenerative changes in AD by increasing the aspartyl protease β-site AβPP cleaving enzyme 1 (BACE1) and amyloid-β (Aβ) genesis...
March 18, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28302486/mitochondria-are-devoid-of-amyloid-%C3%AE-protein-a%C3%AE-producing-secretases-evidence-for-unlikely-occurrence-within-mitochondria-of-a%C3%AE-generation-from-amyloid-precursor-protein
#19
Naomi Mamada, Daisuke Tanokashira, Kazuhiro Ishii, Akira Tamaoka, Wataru Araki
Mitochondrial dysfunction is implicated in the pathological mechanism of Alzheimer's disease (AD). Amyloid β-protein (Aβ), which plays a central role in AD pathogenesis, is reported to accumulate within mitochondria. However, a question remains as to whether Aβ is generated locally from amyloid precursor protein (APP) within mitochondria. We investigated this issue by analyzing the expression patterns of APP, APP-processing secretases, and APP metabolites in mitochondria separated from human neuroblastoma SH-SY5Y cells and those expressing Swedish mutant APP...
April 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28296235/the-circular-rna-cirs-7-promotes-app-and-bace1-degradation-in-an-nf-%C3%AE%C2%BAb-dependent-manner
#20
Zhemin Shi, Ting Chen, Qingbin Yao, Lina Zheng, Zhen Zhang, Jingzhao Wang, Zhimei Hu, Hongmei Cui, Yawei Han, Xiaohui Han, Kun Zhang, Wei Hong
The aberrant accumulation of β-amyloid peptide (Aβ) in the brain is a key feature of Alzheimer's disease (AD), and enhanced cleavage of β-amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) has a major causative role in AD. Despite their prominence in AD pathogenesis, the regulation of BACE1 and APP is incompletely understood. In this study, we report that the circular RNA circular RNA sponge for miR-7 (ciRS-7) has an important role in regulating BACE1 and APP protein levels. Previous studies have shown that ciRS-7, which is highly expressed in the human brain, is down-regulated in the brain of people with AD but the relevance of this finding was not clear...
April 2017: FEBS Journal
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