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Alzheimer's BACE clinical trial

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
Kaichuan Zhu, Finn Peters, Severin Filser, Jochen Herms
Alzheimer's disease is the most prevalent neurodegenerative disorder among elderly persons. Overt accumulation and aggregation of the amyloid-β peptide (Aβ) is thought to be the initial causative factor for Alzheimer's disease. Aβ is produced by sequential proteolytic cleavage of the amyloid precursor protein. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the initial and rate-limiting protease for the generation of Aβ. Therefore, inhibiting BACE1 is considered one of the most promising therapeutic approaches for potential treatment of Alzheimer's disease...
October 1, 2018: Biological Psychiatry
Chinthalapally V Rao, Mudassir Farooqui, Yuting Zhang, Adam S Asch, Hiroshi Y Yamada
Spontaneous late-onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early-onset AD (EOAD) models that rely on forcible expression of AD-associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials...
June 25, 2018: Aging Cell
Vladimir Volloch, Sophia Rits
The present review analyzes the results of recent clinical trials of β secretase inhibition in sporadic Alzheimer's disease (SAD), considers the striking dichotomy between successes in tests of β-site Amyloid Precursor Protein-Cleaving Enzyme (BACE) inhibitors in healthy subjects and familial Alzheimer's disease (FAD) models versus persistent failures of clinical trials and interprets it as a confirmation of key predictions for a mechanism of amyloid precursor protein (APP)-independent, β secretase inhibition-resistant production of β amyloid in SAD, previously proposed by us...
June 2, 2018: Medical Sciences: Open Access Journal
Michael F Egan, James Kost, Pierre N Tariot, Paul S Aisen, Jeffrey L Cummings, Bruno Vellas, Cyrille Sur, Yuki Mukai, Tiffini Voss, Christine Furtek, Erin Mahoney, Lyn Harper Mozley, Rik Vandenberghe, Yi Mo, David Michelson
BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease...
May 3, 2018: New England Journal of Medicine
Devendra Kumar, Ankit Ganeshpurkar, Dileep Kumar, Gyan Modi, Sanjeev Kumar Gupta, Sushil Kumar Singh
Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive loss of memory which is associated with other cognitive deficits. The two protein structures in the brain i.e. neurofibrillary tangles and senile plaques are considered to hamper the normal cognitive activity of the brain. There are various therapeutic interpolations under investigation to thwart and treat AD. Secretases inhibitors are important agents that inhibit the development of senile plaques. β-secretase (BACE) inhibitors are in lime light for the drug development of AD...
March 25, 2018: European Journal of Medicinal Chemistry
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 the 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...
April 26, 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...
June 2017: 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
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