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Alzheimer's BACE clinical trial

Lei Zhang, Laigao Chen, Jason K Dutra, Elizabeth M Beck, Sangram Nag, Akihiro Takano, Nahid Amini, Ryosuke Arakawa, Michael A Brodney, Leanne M Buzon, Shawn D Doran, Lorraine F Lanyon, Timothy J McCarthy, Kelly R Bales, Charles E Nolan, Brian T O'Neill, Klaas Schildknegt, Christer Halldin, Anabella Villalobos
Alzheimer's disease (AD) is characterized by accumulation of β-amyloid (Aβ) plaques and neurofibrillary tau tangles in brain. β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a key role in the generation of Aβ fragments via extracellular cleavage of the amyloid precursor protein (APP). We became interested in developing a BACE1 PET ligand to facilitate clinical assessment of BACE1 inhibitors and explore its potential in the profiling and selection of patients for AD trials. Using a set of PET ligand design parameters, compound 3 (PF-06684511) was rapidly identified as a lead with favorable in vitro attributes and structural handles for PET radiolabeling...
January 22, 2018: Journal of Medicinal Chemistry
Shivani Kumar, Suman Chowdhury, Suresh Kumar
BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace...
October 27, 2017: BMC Neuroscience
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
Shih-Ya Hung, Wen-Mei Fu
Alzheimer's disease (AD) is a major form of senile dementia, characterized by progressive memory and neuronal loss combined with cognitive impairment. AD is the most common neurodegenerative disease worldwide, affecting one-fifth of those aged over 85 years. Recent therapeutic approaches have been strongly influenced by five neuropathological hallmarks of AD: acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of amyloid-β (Aβ plague), formation of intraneuronal neurofibrillary tangles (NTFs), and neuroinflammation...
July 19, 2017: Journal of Biomedical Science
Riqiang Yan
BACE1 was discovered as the β-secretase for initiating the cleavage of amyloid precursor protein (APP) at the β-secretase site, while its close homology BACE2 cleaves APP within the β-amyloid (Aβ) domain region and shows distinct cleavage preferences in vivo. Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer's disease therapy. While BACE1 inhibitors are being tested in advanced clinical trials, knowledge regarding the properties and physiological functions of BACE is highly important and this review summarizes advancements in BACE1 research over the past several years...
2017: Frontiers in Molecular Neuroscience
Maarten Timmers, Soraia Barão, Bianca Van Broeck, Ina Tesseur, John Slemmon, Katja De Waepenaert, Jennifer Bogert, Leslie M Shaw, Sebastiaan Engelborghs, Dieder Moechars, Marc Mercken, Luc Van Nueten, Luc Tritsmans, Bart de Strooper, Johannes Rolf Streffer
The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer's disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers...
2017: Journal of Alzheimer's Disease: JAD
Matthew E Kennedy, Andrew W Stamford, Xia Chen, Kathleen Cox, Jared N Cumming, Marissa F Dockendorf, Michael Egan, Larry Ereshefsky, Robert A Hodgson, Lynn A Hyde, Stanford Jhee, Huub J Kleijn, Reshma Kuvelkar, Wei Li, Britta A Mattson, Hong Mei, John Palcza, Jack D Scott, Michael Tanen, Matthew D Troyer, Jack L Tseng, Julie A Stone, Eric M Parker, Mark S Forman
β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys...
November 2, 2016: Science Translational Medicine
Juliane Schelle, Lisa M Häsler, Jens C Göpfert, Thomas O Joos, Hugo Vanderstichele, Erik Stoops, Eva-Maria Mandelkow, Ulf Neumann, Derya R Shimshek, Matthias Staufenbiel, Mathias Jucker, Stephan A Kaeser
INTRODUCTION: The inhibition of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). We previously reported an age-related increase of tau protein in the cerebrospinal fluid (CSF) of amyloid-β (Aβ) precursor protein (APP) transgenic mice. METHODS: APP transgenic mice were treated with a potent BACE1 inhibitor. CSF tau and CSF Aβ levels were assessed. A novel high-sensitivity tau sandwich immunoassay was developed...
October 14, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Francesco Panza, Davide Seripa, Vincenzo Solfrizzi, Bruno P Imbimbo, Madia Lozupone, Antonio Leo, Rodolfo Sardone, Gaetano Gagliardi, Lucia Lofano, Bianca C Creanza, Paola Bisceglia, Antonio Daniele, Antonello Bellomo, Antonio Greco, Giancarlo Logroscino
Currently available drugs against Alzheimer's disease (AD) target cholinergic and glutamatergic neurotransmissions without affecting the underlying disease process. Putative disease-modifying drugs are in development and target β-amyloid (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease. Areas covered: Phase III clinical studies of emerging anti-Aβ drugs for the treatment of AD were searched in US and EU clinical trial registries and in the medical literature until May 2016...
December 2016: Expert Opinion on Emerging Drugs
Kathryn M Munro, Amelia Nash, Martina Pigoni, Stefan F Lichtenthaler, Jenny M Gunnersen
Inhibition of the protease β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a promising treatment strategy for Alzheimer's disease, and a number of BACE inhibitors are currently progressing through clinical trials. The strategy aims to decrease production of amyloid-β (Aβ) peptide from the amyloid precursor protein (APP), thus reducing or preventing Aβ toxicity. Over the last decade, it has become clear that BACE1 proteolytically cleaves a number of substrates in addition to APP. These substrates are not known to be involved in the pathogenesis of Alzheimer's disease but have other roles in the developing and/or mature central nervous system...
November 2016: Journal of Molecular Neuroscience: MN
Gang Luo, Hongxia Xu, Yinuo Huang, Dapeng Mo, Ligang Song, Baixue Jia, Bo Wang, Zhanqiang Jin, Zhongrong Miao
The main causes of Alzheimer's disease remain elusive. Previous data have implicated the BACE-1 protein as a central player in the pathogenesis of Alzheimer's disease. However, many inhibitors of BACE-1 have failed during preclinical and clinical trials for AD treatment. Therefore, uncovering the exact role of BACE-1 in AD may have significant impact on the future development of therapeutic agents. Three- and six-month-old female APP/PS1 double transgenic mice were used to study abnormal accumulation of BACE-1 protein in brains of mice here...
2016: BioMed Research International
Jeremy H Toyn, Kenneth M Boy, Joseph Raybon, Jere E Meredith, Alan S Robertson, Valerie Guss, Nina Hoque, Francis Sweeney, Xiaoliang Zhuo, Wendy Clarke, Kimberly Snow, R Rex Denton, Dmitry Zuev, Lorin A Thompson, John Morrison, James Grace, Flora Berisha, Michael Furlong, Jun-Sheng Wang, Kimberly A Lentz, Ramesh Padmanabha, Lynda Cook, Cong Wei, Dieter M Drexler, John E Macor, Charlie F Albright, Maciej Gasior, Richard E Olson, Quan Hong, Holly D Soares, Malaz AbuTarif, Michael K Ahlijanian
The amyloid-β peptide (Aβ)-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37...
July 2016: Journal of Pharmacology and Experimental Therapeutics
Genevieve Evin
Alzheimer's disease (AD) is the primary cause of dementia in the elderly. It remains incurable and poses a huge socio-economic challenge for developed countries with an aging population. AD manifests by progressive decline in cognitive functions and alterations in behaviour, which are the result of the extensive degeneration of brain neurons. The AD pathogenic mechanism involves the accumulation of amyloid beta peptide (Aβ), an aggregating protein fragment that self-associates to form neurotoxic fibrils that trigger a cascade of cellular events leading to neuronal injury and death...
June 2016: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
Navya Raj, Agnes Helen, N Manoj, G Harish, Vipin Thomas, Shailja Singh, Seema Sehrawat, Shaguna Seth, Achuthsankar S Nair, Abhinav Grover, Pawan K Dhar
Peptides are increasingly used as inhibitors of various disease specific targets. Several naturally occurring and synthetically developed peptides are undergoing clinical trials. Our work explores the possibility of reusing the non-expressing DNA sequences to predict potential drug-target specific peptides. Recently, we experimentally demonstrated the artificial synthesis of novel proteins from non-coding regions of Escherichia coli genome. In this study, a library of synthetic peptides (Synpeps) was constructed from 2500 intergenic E...
June 2015: Systems and Synthetic Biology
Erik Portelius, Robert A Dean, Ulf Andreasson, Niklas Mattsson, Anni Westerlund, Maria Olsson, Ronald Bradley Demattos, Margaret M Racke, Henrik Zetterberg, Patrick C May, Kaj Blennow
INTRODUCTION: The β-secretase enzyme, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory Aβ biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of Aβ1-34 together with increased Aβ5-40, suggesting that these Aβ species may be novel pharmacodynamic biomarkers in clinical trials...
2014: Alzheimer's Research & Therapy
Helmut Jacobsen, Laurence Ozmen, Antonello Caruso, Robert Narquizian, Hans Hilpert, Bjoern Jacobsen, Dick Terwel, An Tanghe, Bernd Bohrmann
Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors. Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aβ. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment...
August 27, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Sneha B Bansode, Asis K Jana, Kedar B Batkulwar, Shrikant D Warkad, Rakesh S Joshi, Neelanjana Sengupta, Mahesh J Kulkarni
Alzheimer's disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning of existing non-toxic drugs could dramatically reduce the time and costs involved in developmental and clinical trial stages. In this study, preliminary screening of 140 FDA approved nervous system drugs by docking suggested the viability of the tricyclic group of antidepressants against three major AD targets, viz...
2014: PloS One
Mingshan Niu, Jin Hu, Sijin Wu, Zhang Xiaoe, Huaxi Xu, Yunwu Zhang, Jie Zhang, Yongliang Yang
β-secretase (BACE-1) is a potential target for the treatment of Alzheimer's disease (AD). Despite its potential, only few compounds targeting BACE have entered the clinical trials. Herein, we describe the identification of Gefitinib as a potential lead compound for BACE through an integrated approach of structural bioinformatics analysis, experimental assessment and computational analysis. In particular, we performed ELISA and western analysis to assess the effect of Gefitinib using N2a human APP695 cells...
January 2014: Chemical Biology & Drug Design
Christopher Southan, John M Hancock
The beta amyloid (APP) cleaving enzyme (BACE1) has been a drug target for Alzheimer's Disease (AD) since 1999 with lead inhibitors now entering clinical trials. In 2011, the paralog, BACE2, became a new target for type II diabetes (T2DM) having been identified as a TMEM27 secretase regulating pancreatic β cell function. However, the normal roles of both enzymes are unclear. This study outlines their evolutionary history and new opportunities for functional genomics. We identified 30 homologs (UrBACEs) in basal phyla including Placozoans, Cnidarians, Choanoflagellates, Porifera, Echinoderms, Annelids, Mollusks and Ascidians (but not Ecdysozoans)...
2013: Frontiers in Genetics
Jaspreet Kaur Dhanjal, Sukriti Goyal, Sudhanshu Sharma, Rabia Hamid, Abhinav Grover
Alzheimer's is a neurodegenerative disorder resulting in memory loss and decline in cognitive abilities. Accumulation of extracellular beta amyloidal plaques is one of the major pathology associated with this disease. β-Secretase or BACE-1 performs the initial and rate limiting step of amyloidic pathway in which 37-43 amino acid long peptides are generated which aggregate to form plaques. Inhibition of this enzyme offers a viable prospect to check the growth of these plaques. Numerous efforts have been made in recent years for the generation of BACE-1 inhibitors but many of them failed during the preclinical or clinical trials due to drug related or drug induced toxicity...
January 17, 2014: Biochemical and Biophysical Research Communications
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