Search results for: BACE1 Antibody
#35408913 2022/03/24 To Up
The Cell Adhesion Molecule L1 Interacts with Methyl CpG Binding Protein 2 via Its Intracellular Domain.Cell adhesion molecule L1 regulates multiple cell functions, and L1 deficiency is linked to several neural diseases. Recently, we have identified methyl CpG binding protein 2 (MeCP2) as a potential binding partner of the intracellular L1 domain. By ELISA we show here that L1's intracellular domain binds directly to MeCP2 via the sequence motif KDET. Proximity ligation assay with cultured cerebellar and cortical neurons suggests a close association between L1 and MeCP2 in nuclei of neurons. Immunoprecipitation using MeCP2 antibodies and nuclear mouse brain extracts indicates that MeCP2 interacts with an L1 fragment of ~55 kDa (L1-55). Proximity ligation assay indicates that metalloproteases, Î²-site of amyloid precursor protein cleaving enzyme (BACE1) and É£-secretase, are involved in the generation of L1-55. Reduction in MeCP2 expression by siRNA decreases L1-dependent neurite outgrowth from cultured cortical neurons as well as the migration of L1-expressing HEK293 cells. Moreover, L1 siRNA, MeCP2 siRNA, or a cell-penetrating KDET-containing L1 peptide leads to reduced levels of myocyte enhancer factor 2C (Mef2c) mRNA and protein in cortical neurons, suggesting that the MeCP2/L1 interaction regulates Mef2c expression. Altogether, the present findings indicate that the interaction of the novel fragment L1-55 with MeCP2 affects L1-dependent functions, such as neurite outgrowth and neuronal migration.
Gabriele Loers, Ralf Kleene, Maria Girbes Minguez, Melitta Schachner
1608 related Products with: The Cell Adhesion Molecule L1 Interacts with Methyl CpG Binding Protein 2 via Its Intracellular Domain.96tests 100ul100ul2500 assays100ug Lyophilized96tests100 ul100ug Lyophilized250ul1000
#35402415 2022/03/24 To Up
Electrochemical Detection of Alzheimer's Disease Biomarker, Î²-Secretase Enzyme (BACE1), With One-Step Synthesized Reduced Graphene Oxide.Î²-Secretase1 (BACE1) catalyzes the rate-limiting step in the generation of amyloid-Î² peptides, that is, the principal component involved in the pathology of Alzheimer's disease (AD). Recent research studies show correlation between blood and cerebrospinal fluid (CSF) levels of BACE1 with the pathophysiology of AD. In this study, we report one-step synthesized reduced graphene oxide (rGO), activated carbodiimide chemistry, conjugated with BACE1 antibody (Ab), and immobilized on fluorine-doped tin oxide (FTO) electrodes for rapid detection of BACE1 antigen (Ag) for AD diagnosis. The synthesis and fabrication steps were characterized using different types of spectroscopic, X-ray analytic, microscopic, and voltametric techniques. Various parameters including nanomaterial/Ab concentration, response time, pH, temperature, and rate of scan were standardized for maximum current output using the modified electrode. Final validation was performed detection of BACE1 Ag ranging from 1 fM to 1Â ÂµM, with a detection limit of 0.64Â fM in buffer samples and 1Â fM in spiked serum samples, as well as negligible cross-reactivity with neurofilament Ag in buffer, spiked serum, and spiked artificial CSF. The proposed immunosensor gave a quick result in 30Â s, and good repeatability and storage stability for a month, making it a promising candidate for sensitive, specific, and early diagnosis of AD. Thus, the fabricated electrochemical biosensor for BACE-1 detection improves detection performance compared to existing sensors as well as reduces detection time and cost, signifying its potential in early diagnosis of AD in clinical samples.
Jhilik Dey, Akanksha Roberts, Subhasis Mahari, Sonu Gandhi, Prem Prakash Tripathi
2185 related Products with: Electrochemical Detection of Alzheimer's Disease Biomarker, Î²-Secretase Enzyme (BACE1), With One-Step Synthesized Reduced Graphene Oxide.100μg96 tests100μg96 tests96 tests100μg96 tests
#35352880 2022/03/30 To Up
AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model.Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood-brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB-crossing adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS. As a proof-of-concept, we explored the potential of AAV-delivered VHH to inhibit BACE1, a well-characterized target in Alzheimer's disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH-B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity inÂ vitro. We further demonstrate that a single systemic dose of AAV-VHH-B9 produces positive long-term (12âmonths plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the App Alzheimer's mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.
Marika Marino, Lujia Zhou, Melvin Y Rincon, Zsuzsanna Callaerts-Vegh, Jens Verhaert, JÃ©rÃ´me Wahis, Eline Creemers, Lidia Yshii, Keimpe Wierda, Takashi Saito, Catherine Marneffe, Iryna Voytyuk, Yessica Wouters, Maarten Dewilde, Sandra I DuquÃ©, CÃ©cile Vincke, Yona Levites, Todd E Golde, Takaomi C Saido, Serge Muyldermans, Adrian Liston, Bart De Strooper, Matthew G Holt
1469 related Products with: AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model.50 UG
#35241726 2022/03/03 To Up
The neuronal-specific isoform of BIN1 regulates Î²-secretase cleavage of APP and AÎ² generation in a RIN3-dependent manner.Genome-wide association studies have identified BIN1 (Bridging integrator 1) and RIN3 (Ras and Rab interactor 3) as genetic risk factors for late-onset Alzheimer's disease (LOAD). The neuronal isoform of BIN1 (BIN1V1), but not the non-neuronal isoform (BIN1V9), has been shown to regulate tau-pathology and AÎ² generation via RAB5-mediated endocytosis in neurons. BIN1 directly interacts with RIN3 to initiate RAB5-mediated endocytosis, which is essential for Î²-secretase (BACE1)-mediated Î²-secretase cleavage of Î²-amyloid precursor protein (APP) to generate Amyloid-Î² (AÎ²), the key component of senile plaques in AD. Understanding the regulatory roles of BIN1 (neuronal BIN1V1) and RIN3 in Î²-secretase mediated cleavage of APP and AÎ² generation is key to developing novel therapeutics to delay or prevent AD progression. Neuronal and non-neuronal isoforms of BIN1 (BIN1V1 and BIN1V9, respectively) were introduced with RIN3 into an in vitro cell-based system to test RIN3-dependent effects of neuronal BIN1V1 and non-neuronal BIN1V9 on Î²-secretase-mediated cleavage of APP and AÎ² generation. Confocal microscopy was performed to examine RIN3-dependent subcellular localization of BIN1V1 and BIN1V9. Western blot analysis was performed to assess the effects of RIN3 and BIN1V1/BIN1V9 on Î²-secretase mediated processing of APP. We enriched cells expressing BIN1V1 without or with RIN3 via FACS to measure AÎ² generation using AÎ² ELISA assay, and to evaluate APP internalization by chasing biotinylated or antibody-labeled cell surface APP. Neuronal BIN1V1 containing the CLAP domain and non-neuronal BIN1V9 lacking the CLAP domain are the major isoforms present in the brain. Employing confocal microscopy, we showed that RIN3 differentially regulates the recruitment of both BIN1V1 and BIN1V9 into RAB5-endosomes. We further showed that BIN1V1, but not BIN1V9, downregulates Î²-secretase (BACE1)-mediated processing of APP in a RIN3-dependent manner. Overexpression of BIN1V1 also attenuated AÎ² generation in a RIN3-dependent manner. Using cell-based internalization assays, we show BIN1V1, but not BIN1V9, delays the endocytosis of APP, but not of BACE1, into early endosomes, thereby spatially and temporally separating these two proteins into different cellular compartments, resulting in reduced cleavage of APP by BACE1 and reduced AÎ² generation-all in a RIN3-dependent manner. Finally, we show that RIN3 sequesters BIN1V1 in RAB5-positive early endosomes, likely via the CLAP-domain, resulting in attenuated Î²-secretase processing of APP and AÎ² generation by delaying endocytosis of APP. Our findings provide new mechanistic data on how two AD-associated molecules, RIN3 and BIN1 (neuronal BIN1V1), interact to govern AÎ² production, implicating these two proteins as potential therapeutic targets for the prevention and treatment of AD.
Raja Bhattacharyya, Catarina Amelia Fidalgo Teves, Alexandra Long, Madison Hofert, Rudolph E Tanzi
2036 related Products with: The neuronal-specific isoform of BIN1 regulates Î²-secretase cleavage of APP and AÎ² generation in a RIN3-dependent manner.100ul 100ul 100ul4 Arrays/Slide100 25 mg
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BACE1 Overexpression Reduces SH-SY5Y Cell Viability Through a Mechanism Distinct from Amyloid-Î² Peptide Accumulation: Beta Prime-Mediated Competitive Depletion of sAÎ²PPÎ±.The Alzheimer's disease (AD)-associated amyloid-beta protein precursor (AÎ²PP) can be cleaved by Î²-site AÎ²PP cleaving enzyme 1 (BACE1) and the Î³-secretase complex to yield neurotoxic amyloid-Î² (AÎ²) peptides. However, AÎ²PP can also be cleaved in a 'non-amyloidogenic' manner either by Î±-secretase to produce soluble AÎ²PP alpha (sAÎ²PPÎ±) (a fragment with neuroprotective/neurogenic functions) or through alternative BACE1-mediated 'beta prime' activity yielding soluble AÎ²PP beta prime (sAÎ²PPÎ²').
Lauren Owens, Joshua Bracewell, Alexandre Benedetto, Neil Dawson, Christopher Gaffney, Edward Parkin
1579 related Products with: BACE1 Overexpression Reduces SH-SY5Y Cell Viability Through a Mechanism Distinct from Amyloid-Î² Peptide Accumulation: Beta Prime-Mediated Competitive Depletion of sAÎ²PPÎ±.96 tests100ug1000 assays100ug Lyophilized96 tests100ug100 100ug50 ug100ug96 tests100μg
#34360799 2021/07/27 To Up
Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF.Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disease, causing motor and cognitive dysfunction and dementia. iNPH and Alzheimer's disease (AD) share similar molecular characteristics, including amyloid deposition, t-tau and p-tau dysregulation; however, the disease is under-diagnosed and under-treated. The aim was to identify a panel of sphingolipids and proteins in CSF to diagnose iNPH at onset compared to aged subjects with cognitive integrity (C) and AD patients by adopting multiple reaction monitoring mass spectrometry (MRM-MS) for sphingolipid quantitative assessment and advanced high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomic analysis. The results indicated that iNPH are characterized by an increase in very long chains Cer C22:0, Cer C24:0 and Cer C24:1 and of acute-phase proteins, immunoglobulins and complement component fragments. Proteins involved in synaptic signaling, axogenesis, including BACE1, APP, SEZ6L and SEZ6L2; secretory proteins (CHGA, SCG3 and VGF); glycosylation proteins (POMGNT1 and DAG1); and proteins involved in lipid metabolism (APOH and LCAT) were statistically lower in iNPH. In conclusion, at the disease onset, several factors contribute to maintaining cell homeostasis, and the protective role of very long chains sphingolipids counteract overexpression of amyloidogenic and neurotoxic proteins. Monitoring specific very long chain Cers will improve the early diagnosis and can promote patient follow-up.
Enrica Torretta, Beatrice Arosio, Pietro Barbacini, Daniele Capitanio, Paolo Dionigi Rossi, Manuela Moriggi, Mario Clerici, Daniela Mari, Matteo Cesari, Cecilia Gelfi
2231 related Products with: Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF.3 inhibitors
#34102967 // To Up
An Overview of Î²-Amyloid Cleaving Enzyme 1 (BACE1) in Alzheimer's Disease Therapy: Elucidating its Exosite-Binding Antibody and Allosteric Inhibitor.Over decades of its identification, numerous past and ongoing research has focused on Î²- amyloid cleaving enzyme 1 (BACE1) therapeutic roles as a target in treating Alzheimer's disease (AD). Although the initial BACE1 inhibitors at phase-3 clinical trials tremendously reduced Î² -amyloidassociated plaques in patients with AD, the researchers eventually discontinued the tests for lack of potency. This discontinuation has resulted in limited drug development and discovery targeted at BACE1, despite the high demand for dementia and AD therapies. It is, therefore, imperative to describe the detailed underlying biological basis of the BACE1 therapeutic option in neurological diseases. Herein, we highlight BACE1 bioactivity, genetic properties, and role in neurodegenerative therapy. We review research contributions on BACE1 exosite-binding antibody and allosteric inhibitor development as AD therapies. The review also covers BACE1 biological function, the disease-associated mechanisms, and the enzyme conditions for amyloid precursor protein site splitting. Based on the present review, we suggest further studies on anti-BACE1 exosite antibodies and BACE1 allosteric inhibitors. Non-active site inhibition might be the way forward to BACE1 therapy in Alzheimer's neurological disorder.
Samuel C Ugbaja, Monsurat M Lawal, Hezekiel M Kumalo
2011 related Products with: An Overview of Î²-Amyloid Cleaving Enzyme 1 (BACE1) in Alzheimer's Disease Therapy: Elucidating its Exosite-Binding Antibody and Allosteric Inhibitor.100μg100μg100μg 100ul 100ul 100ul 100ul 100ul 100ul50ug100ug Lyophilized 100ul
#33848635 2021/04/10 To Up
Passive immunotherapy with a novel antibody against 3pE-modified AÎ² demonstrates potential for enhanced efficacy and favorable safety in combination with BACE inhibitor treatment in plaque-depositing mice.The imbalance between production and clearance of amyloid Î² (AÎ²) peptides and their resulting accumulation in the brain is an early and crucial step in the pathogenesis of Alzheimer's disease (AD). Therefore, AÎ² is strongly positioned as a promising and extensively validated therapeutic target for AD. Investigational disease-modifying approaches aiming at reducing cerebral AÎ² concentrations include prevention of de novo production of AÎ² through inhibition of Î²-site amyloid precursor protein cleaving enzyme 1 (BACE1), and clearance of AÎ² deposits via passive AÎ² immunotherapy. We have developed a novel, high affinity antibody against AÎ² peptides bearing a pyroglutamate residue at amino acid position 3 (3pE), an AÎ² species abundantly present in plaque deposits in AD brains. Here, we describe the preclinical characterization of this antibody, and demonstrate a significant reduction in amyloid burden in the absence of microhemorrhages in different mouse models with established plaque deposition. Moreover, we combined antibody treatment with chronic BACE1 inhibitor treatment and demonstrate significant clearance of pre-existing amyloid deposits in transgenic mouse brain, without induction of microhemorrhages and other histopathological findings. Together, these data confirm significant potential for the 3pE-specific antibody to be developed as a passive immunotherapy approach that balances efficacy and safety. Moreover, our studies suggest further enhanced treatment efficacy and favorable safety after combination of the 3pE-specific antibody with BACE1 inhibitor treatment.
Jonathan Janssens, Bart Hermans, Marc Vandermeeren, Erio Barale-Thomas, Marianne Borgers, Roland Willems, Greet Meulders, Cindy Wintmolders, Dries Van den Bulck, Astrid Bottelbergs, Luc Ver Donck, Peter Larsen, Dieder Moechars, Wilson Edwards, Marc Mercken, Bianca Van Broeck
2238 related Products with: Passive immunotherapy with a novel antibody against 3pE-modified AÎ² demonstrates potential for enhanced efficacy and favorable safety in combination with BACE inhibitor treatment in plaque-depositing mice.100 µg100ug Lyophilized100 100ug Lyophilized100μg100ug Lyophilized100ug Lyophilized1 Set100ug Lyophilized200ul100ug Lyophilized100 µg
#33848613 2021/04/10 To Up
Characterization of monomeric and soluble aggregated AÎ² in Down's syndrome and Alzheimer's disease brains.The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (AÎ²) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the AÎ² peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different AÎ² species including oligomeric AÎ². Mass spectrometry was then used to evaluate the presence of AÎ² species in the different patient groups. A large number of AÎ² peptides were identified including AÎ²1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and AÎ² peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the AÎ² sequence APP/AÎ²(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most AÎ² peptides had higher abundance in AD and DS compared to controls, except the APP/AÎ²(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AÎ²X-40 and AÎ²X-34 were increased in DS compared with AD. AÎ²1-40, AÎ²1-42, and AÎ²4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative AÎ²1-42 signals were obtained compared with samples IP'd with 6E10â+â4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All AÎ² peptides found in AD were also present in DS indicating similar pathways of AÎ² peptide production, degradation and accumulation, except for APP/AÎ²(-X to 15). Likewise, the AÎ² peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.
Eleni Gkanatsiou, Charlotte Sahlin, Erik Portelius, Malin Johannesson, Linda SÃ¶derberg, Johanna FÃ¤lting, Hans Basun, Christer MÃ¶ller, Tomas Odergren, Henrik Zetterberg, Kaj Blennow, Lars Lannfelt, Gunnar Brinkmalm
2796 related Products with: Characterization of monomeric and soluble aggregated AÎ² in Down's syndrome and Alzheimer's disease brains.96 tests1-99 mg/ml/ea price x 296 tests96 tests96 tests1-99 mg/ml/ea price x 250 ug 100ug500 tests
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Dynamic Docking Using Multicanonical Molecular Dynamics: Simulating Complex Formation at the Atomistic Level.Multicanonical molecular dynamics (McMD)-based dynamic docking has been applied to predict the native binding configurations for several protein receptors and their ligands. Due to the enhanced sampling capabilities of McMD, it can exhaustively sample bound and unbound ligand configurations, as well as receptor conformations, and thus enables efficient sampling of the conformational and configurational space, not possible using canonical MD simulations. As McMD samples a wide configurational space, extensive analysis is required to study the diverse ensemble consisting of bound and unbound structures. By projecting the reweighted ensemble onto the first two principal axes obtained via principal component analysis of the multicanonical ensemble, the free energy landscape (FEL) can be obtained. Further analysis produces representative structures positioned at the local minima of the FEL, where these structures are then ranked by their free energy. In this chapter, we describe our dynamic docking methodology, which has successfully reproduced the native binding configuration for small compounds, medium-sized compounds, and peptide molecules.
Gert-Jan Bekker, Narutoshi Kamiya
1902 related Products with: Dynamic Docking Using Multicanonical Molecular Dynamics: Simulating Complex Formation at the Atomistic Level.100 μg1 mg100ul100μl0.2 mg250ul100ul5 g0.1mg100ul
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