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George Nicolae Daniel Ion, Dragos Paul Mihai, Gina Lupascu, George Mihai Nitulescu
Targeting beta-secretase 1, also known as beta-amyloid precursor protein cleaving enzyme (BACE-1) for the inhibition of amyloid production has been intensely studied in the last decades in the search for stopping Alzheimer's disease progression. The chances of finding a druggable BACE-1 inhibitor may be increased by drug repurposing, as this kind of molecules already fulfil certain requirements needed for further advancement. The study describes the development and application of a data mining method based on molecular frameworks and descriptor values of tested BACE-1 inhibitors, suitable for filtering large compound databases, in order to find molecules with high potency against this protease...
September 20, 2018: Journal of Biomolecular Structure & Dynamics
Chinthalapally V Rao, Mudassir Farooqui, Adam S Asch, Hiroshi Y Yamada
From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue...
September 20, 2018: Cell Cycle
Ulf Neumann, Mike Ufer, Laura H Jacobson, Marie-Laure Rouzade-Dominguez, Gunilla Huledal, Carine Kolly, Rainer M Lüönd, Rainer Machauer, Siem J Veenstra, Konstanze Hurth, Heinrich Rueeger, Marina Tintelnot-Blomley, Matthias Staufenbiel, Derya R Shimshek, Ludovic Perrot, Wilfried Frieauff, Valerie Dubost, Hilmar Schiller, Barbara Vogg, Karen Beltz, Alexandre Avrameas, Sandrine Kretz, Nicole Pezous, Jean-Michel Rondeau, Nicolau Beckmann, Andreas Hartmann, Stefan Vormfelde, Olivier J David, Bruno Galli, Rita Ramos, Ana Graf, Cristina Lopez Lopez
The beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-β (Aβ), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Aβ therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aβ in rats and dogs, and Aβ plaque deposition in APP-transgenic mice...
September 17, 2018: EMBO Molecular Medicine
Andrew Cubbon, Ivana Ivancic-Bace, Edward L Bolt
Co-opting of CRISPR-Cas 'Interference' reactions for editing the genomes of eukaryotic and prokaryotic cells has highlighted crucial support roles for DNA repair systems that strive to maintain genome stability. As front-runners in genome editing that targets DNA, the class 2 CRISPR-Cas enzymes Cas9 and Cas12a rely on repair of DNA double-strand breaks (DDSBs) by host DNA repair enzymes, using mechanisms that vary in how well they are understood. Data are emerging about the identities of DNA repair enzymes that support genome editing in human cells...
October 31, 2018: Bioscience Reports
Marin Radovcic, Tom Killelea, Ekaterina Savitskaya, Lukas Wettstein, Edward L Bolt, Ivana Ivancic-Bace
Prokaryotic adaptive immunity is established against mobile genetic elements (MGEs) by 'naïve adaptation' when DNA fragments from a newly encountered MGE are integrated into CRISPR-Cas systems. In Escherichia coli, DNA integration catalyzed by Cas1-Cas2 integrase is well understood in mechanistic and structural detail but much less is known about events prior to integration that generate DNA for capture by Cas1-Cas2. Naïve adaptation in E. coli is thought to depend on the DNA helicase-nuclease RecBCD for generating DNA fragments for capture by Cas1-Cas2...
September 5, 2018: Nucleic Acids Research
Julia Relat, Julio Come, Belen Perez, Pelayo Camps, Diego Muñoz-Torrero, Albert Badia, Lydia Gimenez-Llort, M Victòria Clos
Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice...
September 4, 2018: International Journal of Molecular Sciences
Alberto Martínez, Mai Zahran, Miguel Gomez, Coreen Cooper, Johnny Guevara, Erik Ekengard, Ebbe Nordlander, Ralph Alcendor, Sarah Hambleton
The lack of any effective therapy along with the aging world population anticipates a growth of the worldwide incidence of Alzheimer's disease (AD) to more than 100 million cases by 2050. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. In the amyloidogenic process, a β-secretase, known as BACE 1, plays a fundamental role in the production of Aβ fragments, and therefore, inhibition of such enzymes represents a major strategy for the rational design of anti-AD drugs...
September 15, 2018: Bioorganic & Medicinal Chemistry
Chiara Fenoglio, Emanuela Oldoni, Maria Serpente, Milena A De Riz, Marina Arcaro, Marianna D'Anca, Anna M Pietroboni, Alberto Calvi, Elisabetta Lecchi, An Goris, Klara Mallants, Bénédicte Dubois, Cristoforo Comi, Roberto Cantello, Elio Scarpini, Daniela Galimberti
LncRNA PCR arrays containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from a discovery population of patients with MS. Data from discovery and replications cohorts showed a generalized dysregulation of lncRNA levels in MS patients compared with controls. MALAT1, MEG9, NRON, ANRIL, TUG1, XIST, SOX2OT, GOMAFU, HULC, BACE-1AS were significantly downregulated in MS patients in comparison with controls. Therefore, we performed a validation analysis in an independent cohort of Belgian origin...
August 27, 2018: Journal of Neuroimmunology
Sarah R Murray, Julius Juodakis, Jonas Bacelis, Anna Sand, Jane E Norman, Verena Sengpiel, Bo Jacobsson
INTRODUCTION: Preterm delivery is a major global public health challenge. The objective of this study was to determine how the preterm delivery rates differ throughout a country of very high human-development index and to explore rural versus urban environmental and socio-economic factors which might be responsible for this variation. MATERIAL AND METHODS: A population-based study was performed using data from the Swedish Medical Birth Register 1998 to 2013. Sweden was chosen as a model because of its validated routinely collected data and availability of individual social data...
August 31, 2018: Acta Obstetricia et Gynecologica Scandinavica
Toby Prike, Michelle M Arnold, Paul Williamson
Biases in the assessment and integration of evidence are likely contributors to anomalistic (e.g., paranormal, extra-terrestrial) beliefs because of the non-evidence based nature of these beliefs. However, little research has examined the relationship between anomalistic beliefs and evidence integration biases. The current study addressed this gap by examining the relationship between anomalistic belief and four such biases; bias against disconfirmatory evidence (BADE), bias against confirmatory evidence (BACE), liberal acceptance bias, and the jumping to conclusions bias (JTC)...
August 23, 2018: Acta Psychologica
Maarten Timmers, Johannes Rolf Streffer, Alberto Russu, Yushin Tominaga, Hiroko Shimizu, Ayako Shiraishi, Kanaka Tatikola, Pascale Smekens, Anne Börjesson-Hanson, Niels Andreasen, Jorge Matias-Guiu, Miquel Baquero, Mercè Boada, Ina Tesseur, Luc Tritsmans, Luc Van Nueten, Sebastiaan Engelborghs
BACKGROUND: β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. METHODS: In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0...
August 23, 2018: Alzheimer's Research & Therapy
Priyal Barai, Nisith Raval, Sanjeev Acharya, Ankit Borisa, Hardik Bhatt, Niyati Acharya
Alzheimer's disease (AD) is an enervating and chronic progressive neurodegenerative disorder, occurring frequently in the elderly and adversely affecting intellectual capabilities and the cognitive processes. Bergenin possesses efficacious antioxidant, antiulcerogenic, anti-HIV, hepatoprotective, neuroprotective, anti-inflammatory and immunomodulatory activity along with antinociceptive effect and wound healing properties. Previous studies have shown that bergenin has in vitro bovine adrenal tyrosine hydroxylase inhibitory activity, mushroom tyrosinase inhibitory activities, β-secretase (BACE-1) enzyme inhibitory activity and prevented neuronal death in the primary culture of rat cortical neurons...
August 14, 2018: Behavioural Brain Research
Tamas Fulop, Jacek M Witkowski, Karine Bourgade, Abdelouahed Khalil, Echarki Zerif, Anis Larbi, Katsuiku Hirokawa, Graham Pawelec, Christian Bocti, Guy Lacombe, Gilles Dupuis, Eric H Frost
Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease...
2018: Frontiers in Aging Neuroscience
Moustafa T Gabr, Mohammed S Abdel-Raziq
A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC50 value of 14.7 nM) and BACE-1 inhibition (IC50 value of 13.1 nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1...
September 15, 2018: Bioorganic & Medicinal Chemistry Letters
Ge Zhang, Amit Srivastava, Jonas Bacelis, Julius Juodakis, Bo Jacobsson, Louis J Muglia
The fine control of birth timing is important to human survival and evolution. A key challenge in studying the mechanisms underlying the regulation of human birth timing is that human parturition is a unique to human event - animal models provide only limited information. The duration of gestation or the risk of preterm birth is a complex human trait under genetic control from both maternal and fetal genomes. Genomic discoveries through genome-wide association (GWA) studies would implicate relevant genes and pathways...
June 15, 2018: Best Practice & Research. Clinical Obstetrics & Gynaecology
Shadab Md, Sook Yee Gan, Yong Hong Haw, Chee Liang Ho, Sinrun Wong, Hira Choudhury
Alzheimer's disease (AD) is an increasingly prevalent neurological disorder of the central nervous system. There is growing evidence that amyloidogenesis is a pathological hallmark for AD; this leads to the formation of senile plaques. Naringenin is a bioflavonoid which has neuroprotective effects through its antioxidant and anti-inflammatory properties. However, its clinical usage is limited due to its inefficient transport across biological membranes. In the present study, a naringenin nanoemulsion was prepared and its neuroprotective effects were tested against β-amyloid induced neurotoxicity in a human neuroblastoma cell line (SH-SY5Y)...
October 15, 2018: International Journal of Biological Macromolecules
Stefan F Lichtenthaler, Marius K Lemberg, Regina Fluhrer
Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions...
August 1, 2018: EMBO Journal
Talha Burki
No abstract text is available yet for this article.
June 23, 2018: Lancet
P S Aisen, E Siemers, D Michelson, S Salloway, C Sampaio, M C Carrillo, R Sperling, R Doody, P Scheltens, R Bateman, M Weiner, B Vellas
Although the results were disappointing from two recent clinical trials of amyloid-targeting drugs in mild-to-moderate AD, the trials provided information that will be important for future studies, according to the EU-US CTAD Task Force, which met in November 2017 to discuss the EXPEDITION3 and EPOCH trials. These trials tested two of the predominant drug development strategies for AD: amyloid immunotherapy and BACE inhibition in populations largely composed of mild AD dementia patients. The results of these trials support the emerging consensus that effective amyloid-targeted treatment will require intervention in early, even pre-symptomatic stages of the disease...
2018: Journal of Prevention of Alzheimer's Disease
Moustafa T Gabr, Mohammed S Abdel-Raziq
Multi-target-directed ligands (MTDLs) centered on β-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site...
October 2018: Bioorganic Chemistry
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