Amyloid Precursor Protein Secretases - beta-Secretase Summary Report | CureHunter
Amyloid Precursor Protein Secretases: Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.
In vivo reconstitution of gamma-secretase in Drosophila results in substrate specificity - MDC Repository
The intramembrane aspartyl protease gamma-secretase plays a fundamental role in several signaling pathways involved in cellular differentiation and has been linked with a variety of human diseases, including Alzheimers disease. Here, we describe a transgenic Drosophila model for in vivo-reconstituted gamma-secretase, based on expression of epitope-tagged versions of the four core gamma-secretase components, Presenilin, Nicastrin, Aph-1, and Pen-2. In agreement with previous cell culture and yeast studies, coexpression of these four components promotes the efficient assembly of mature, proteolytically active gamma-secretase. We demonstrate that in vivo-reconstituted gamma-secretase has biochemical properties and a subcellular distribution resembling those of endogenous gamma-secretase. However, analysis of the cleavage of alternative substrates in transgenic-fly assays revealed unexpected functional differences in the activity of reconstituted gamma-secretase toward different substrates, ...
The proteins BACE1 and BACE2 and β-secretase activity in normal and Alzheimers disease brain | Biochemical Society...
The insidious progression of AD (Alzheimers disease) is believed to be linked closely to the production, accumulation and aggregation of the ∼4.5 kDa protein fragment called Aβ (amyloid β-peptide). Aβ is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as β- and γ-secretase. β-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Aβ and was identified 7 years ago as BACE1 (β-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of β-secretase in the normal and AD brain are central to the understanding of excessive production of Aβ in AD, and in targeting and normalizing this β-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased β-secretase activity in AD, with recent findings by our group showing ...
APH1, PEN2, and Nicastrin increase Aβ levels and γ-secretase activity<...
TY - JOUR. T1 - APH1, PEN2, and Nicastrin increase Aβ levels and γ-secretase activity. AU - Marlow, Laura. AU - Canet, Rosa M.. AU - Haugabook, Sharie J.. AU - Hardy, John A.. AU - Lahiri, Debomoy K.. AU - Sambamurti, Kumar. PY - 2003/6/6. Y1 - 2003/6/6. N2 - A major component of the amyloid plaque core in Alzheimers disease (AD) is the 40-42-residue amyloid β peptide (Aβ). Mutations linked to AD such as those in presenilins 1 (PS1) and 2 (PS2) invariably increase the longer Aβ42 species that forms neurotoxic oligomers. It is believed that PS1/2 constitute the catalytic subunit of the γ-secretase responsible for the final step in Aβ biogenesis. Recent genetic studies have identified a number of additional genes encoding APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the γ-secretase complex with PS1. Further, knockout studies using RNAi showed that these components are essential for γ-secretase activity. However, the nature of γ-secretase and how the aforementioned ...
Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor<...
TY - JOUR. T1 - Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor. AU - Gillman, K.W.. AU - Starrett, J.E.. AU - Parker, M.F.. AU - Xie, K.. AU - Bronson, J.J.. AU - Marcin, L.R.. AU - McElhone, K.E.. AU - Bergstrom, C.P.. AU - Mate, R.A.. AU - Williams, Richard. AU - Meredith, J.E.. AU - Burton, C.R.. AU - Barten, D.M.. AU - Toyn, J.H.. AU - Roberts, S.B.. AU - Lentz, K.A.. AU - Houston, J.G.. AU - Zaczek, R.. AU - Albright, C.F.. AU - Decicco, C.P.. AU - Macor, J.E.. AU - Olson, R.E.. PY - 2010/6/10. Y1 - 2010/6/10. N2 - During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimers disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase ...
Beta Secretase 1 (Aspartyl Protease 2 or Beta Site Amyloid Precursor Protein Cleaving Enzyme 1 or Memapsin 2 or Membrane...
Beta Secretase 1 (Aspartyl Protease 2 or Beta Site Amyloid Precursor Protein Cleaving Enzyme 1 or Memapsin 2 or Membrane Associated Aspartic Protease 2 or BACE1 or EC 3.4.23.46) - Pipeline Review, H2 2018
IJMS | Free Full-Text | Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of...
Alzheimers disease (AD) is characterized by extracellular accumulation of amyloid-β peptide (Aβ), generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Aβ generation is inhibited when the initial ectodomain shedding is caused by α-secretase, cleaving APP within the Aβ domain. Therefore, an increase in α-secretase activity is an attractive therapeutic target for AD treatment. APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to influence APP processing. Although several studies have focused on γ-secretase, the effect of the membrane lipid microenvironment on α-secretase is poorly understood. In the present study, we systematically investigated the effect of fatty acid (FA) acyl chain length (10:0, 12:0, 14:0, 16:0, 18:0, 20:0, 22:0, 24:0), membrane polar lipid headgroup (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine), saturation grade and the FA double-bond
Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells
Gamma-secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their intracellular domains to the nucleus. Notch overexpression has been associated with breast, colon, cervical and prostate cancers. We tested the effect of three different gamma-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 muM and above but had a minimal effect on the non-malignant breast lines. GSI1 was also cytotoxic for a wide variety of cancer cell lines in the NCI60 cell screen. GSI1 treatment resulted in a marked decrease in gamma-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the gamma-secretase components or ligands. Flow cytometric and western blot analyses indicated that GSI1 induces a G2/M arrest leading to apoptosis, through downregulation of Bcl-2, Bax and Bcl-XL. GSI1 also inhibited proteasome activity. Thus, the ...
PSENEN - Gamma-secretase subunit PEN-2 - Homo sapiens (Human) - PSENEN gene & protein
Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111).
Women Health: June 2014
Coffee made from the roasted seeds of the genus Coffee, belonging to the family Rubiaceae native to southern Arabia. Coffee may consist certain substances, effecting the risk of Alzheimers disease. AD mice given caffeine in their drinking water from young adulthood into older age showed to inhibit memory and cognitive impairment and lower brain levels of amyloid-beta; Abeta)(24)(25). In mice with Alzheimers disease caused by dysregulated endoplasmic reticulum (ER) calcium (Ca 2+), induced deletion of RyanR3, showed the enhancement of coffee in activation of RyanRs which protected AD neurons from synaptic and network dysfunction(26). Intake of 5 cups of coffee per day(moderate caffeine intake) found to protect against the development of certain cognitive impairment and decreased hippocampal amyloid-beta (Abeta) levels through suppression of both beta-secretase (BACE1), a beta-site amyloid precursor protein cleaving enzyme 1 and presenilin 1 (PS1)/gamma-secretase expression(mutations in the ...
2OHR | X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 6A | 2OHR A | P56817 | BACE1 | Beta-secretase 1 | 3D...
cansSAR 3D Structure of 2OHR | X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 6A | 2OHR_A | Beta-secretase 1 - Also known as BACE1_HUMAN, BACE1, BACE, KIAA1149. Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase (PubMed:10656250, PubMed:10677483, PubMed:20354142). Cleaves CHL1 (By similarity). Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3 (via their VHS domain); the interaction highly increases when BACE1 is phosphorylated at Ser-498 (PubMed:14567678, PubMed:15886016). Interacts with RTN3 and RTN4 (PubMed:15286784, PubMed:16965550, PubMed:16979658). Interacts with SNX6 (PubMed:20354142). Interacts with PCSK9 (PubMed:18660751). Interacts with NAT8 and NAT8B (PubMed
PromoKine - beta-Secretase Fluorometric Assay Kit
β-Secretase (BACE) is a membrane-bound aspartyl protease that cleaves the amyloid precursor protein and is consequently an excellent target for anti-amyloid therapy in the treatment of Alzheimers disease. Finding inhibitors of β-secretase is one of the major goals of Alzheimers disease drug development. PromoKines β-Secretase Fluorometric Assay Kit provides a convenient, non-radioactive system for detecting β-Secretase activity in biological samples. The kit provides active β-Secretase as positive control, β-Secretase inhibitor as negative control, optimized peptide substrate (conjugated to two reporter molecules), and buffers for convenient measurement of β-Secretase activity in mammalian samples. β-Secretase inhibitors are also available separately. ...
Confocal Microscope | Professor Gouttes Lab | Amherst College
We have used the confocal microscope to analyze the subcellular distribution of the APH-1 protein in early embryos of C. elegans. APH-1 is one of four protein members of the gamma-secretase complex, which achieves intramembranous cleavage of a variety of target membrane proteins. Although the effect in protein cleavage is clear, the site of gamma-secretase assembly and function within the cell remains elusive. We use the early C. elegans embryo as the context in which to analyze protein localization because the cells are relatively large, and because the four-cell embryo is the site of a well-defined event of Notch signaling that has been shown to be entirely dependent on gamma-secretase activity. Our analysis of wild type C. elegans embryos shows that the APH-1 protein is present at the plasma membrane in early embryos. This location is consistent with the role of gamma-secretase in targeting the Notch receptor after it has interacted with its ligand on an adjacent cell, and is also consistent ...
Amyloid Precursor Protein Secretases | Colorado PROFILES
Hoffman LM, Fouladi M, Olson J, Daryani VM, Stewart CF, Wetmore C, Kocak M, Onar-Thomas A, Wagner L, Gururangan S, Packer RJ, Blaney SM, Gajjar A, Kun LE, Boyett JM, Gilbertson RJ. Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. Childs Nerv Syst. 2015 Aug; 31(8):1283-9 ...
A new kid on the Alzheimers block | Chemiotics II
Theres a new kid on the Alzheimers block, and it may explain why the huge sums thrown at beta-secretase inhibitors by big pharma has been such an abject failure. First, a lot of technical background. The APP (for amyloid precursor protein) contains anywhere from 563 to 770 amino acids in 5 distinct transcripts made by…
Funktionelle Charakterisierung von BACE, einer für die Alzheimer Krankheit relevanten Protease
Alzheimer`s disease is the most common cause of progressive cognitive decline in the aged population. Pathologically Alzheimer`s disease is characterized by the invariant accumulation of senile plaques. Senile plaques are predominantly composed of the amyloid beta-peptide (A-beta), which is derived from the membrane bound beta-amyloid precursor protein (beta-APP) by sequential proteolytic cleavage. The recently identified beta-secretase (BACE) is responsible for the cleavage at the N-terminus of the A-beta domain. This cleavage generates membrane-bound beta-APP-Cterminal fragments (beta-APP-CTF) which are the immediate precursor for gamma-secretase cleavage and therefore for liberation of A-beta. The present work shows that BACE moves along the secretory pathway, while it undergoes post-translational modifications, which can be monitored by a significant increase in the molecular mass and cleavage of its pro-peptide. BACE becomes N-glycosylated within the ER and the increase in molecular mass is ...
Funktionelle Charakterisierung von BACE, einer für die Alzheimer Krankheit relevanten Protease
Alzheimer`s disease is the most common cause of progressive cognitive decline in the aged population. Pathologically Alzheimer`s disease is characterized by the invariant accumulation of senile plaques. Senile plaques are predominantly composed of the amyloid beta-peptide (A-beta), which is derived from the membrane bound beta-amyloid precursor protein (beta-APP) by sequential proteolytic cleavage. The recently identified beta-secretase (BACE) is responsible for the cleavage at the N-terminus of the A-beta domain. This cleavage generates membrane-bound beta-APP-Cterminal fragments (beta-APP-CTF) which are the immediate precursor for gamma-secretase cleavage and therefore for liberation of A-beta. The present work shows that BACE moves along the secretory pathway, while it undergoes post-translational modifications, which can be monitored by a significant increase in the molecular mass and cleavage of its pro-peptide. BACE becomes N-glycosylated within the ER and the increase in molecular mass is ...
Elucidation of the mechanism of action of Gamma Secretase Modulators - Cure Alzheimers Fund
This project focuses on ultimately defining the structure of a soluble gamma-secretase modulator (SGSM)-bound gamma-secretase enzyme complex at high resolution. Defining the structure of this complex will provide critical information towards elucidating the mechanism of action of this promising ...
RCSB PDB - 3UQR: Crystal structure of BACE1 with its inhibitor Macromolecule Annotations Page
3UQR: Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases
RCSB PDB - 3UQP: Crystal structure of Bace1 with its inhibitor Macromolecule Annotations Page
3UQP: Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases
TCDB » SEARCH
9.B.47 The γ-Secretase (γ-Secretase) Family. γ-secretase is an unusual membrane-embedded protease, which cleaves the transmembrane domains (TMSs) of type I membrane proteins, including amyloid-beta precursor protein and Notch receptor. A hydrophilic pore is formed by TMS6 and TMS7 of presenilin 1 (PS1), the catalytic subunit of γ-secretase. TMS8, TMS9 and the C-terminus of PS1, which encompass the conserved PAL motif and the hydrophobic C-terminal tip, are critical for the catalytic activity and the formation of the γ-secretase complex. The amino acid residues around the PAL motif and the extracellular/luminal portion of TMS9 are highly water accessible and located in proximity to the catalytic pore (Sato et al., 2008). Furthermore, the region starting from the luminal end of TMS9 toward the C terminus forms an amphipathic alpha-helix-like structure that extends along the interface between the membrane and the extracellular milieu. Competition analysis using γ-secretase inhibitors revealed ...
Acute γ-Secretase Inhibition of Nonhuman Primate CNS Shifts Amyloid Precursor Protein (APP) Metabolism from Amyloid-β...
The results of this study demonstrate that Aβ metabolism in the rhesus monkey is similar to healthy humans (Bateman et al., 2006), which is expected because there are no significant amyloid plaques present in the rhesus monkey brain at this age (Struble et al., 1985). In conjunction with in vivo stable-isotope-labeling, new generation of CNS Aβ was significantly reduced in response to γ-secretase inhibition. However, in contrast to the periphery, production of CNS Aβ did not rebound above baseline after cessation of inhibition. Defining the metabolic fate of APP in the CNS is critically important for the development of γ-secretase inhibitors to treat AD, as a substrate build-up of APP fragments could potentially lead to an overshoot in neurotoxic amyloid peptides. The lack of Aβ rebound in the CNS could be attributed to the shunting of APP (possibly β C-terminal fragments, e.g., C99) to γ-secretase independent degradation. In support of this alternative, noncanonical processing, ...
Nicastrin Antibody, pAb, Rabbit Antibody - GenScript
Nicastrin is a Type I transmembrane glycoprotein. Along with presenilin, APH-1, PEN-2, it comprises the multimeric gamma-secretase complex. The gamma-secretase complex can cleave the beta-amyloid (A4) precursor protein and yields amyloid beta peptide, the main component of the neuritic plaque a...
Genetic and host factors for dementia in Downs syndrome | The British Journal of Psychiatry
Although there has been controversy about the relative importance of plaques versus tangles in the development of Alzheimers disease, there is increasing evidence that altered metabolism of Aβ peptides and amyloid deposition in neuritic plaques causes Alzheimers disease by triggering a complex pathological cascade that produces dementia. The Aβ peptides Aβ1-40 and Aβ1-42, the two major species of Aβ, are generated from APP by sequential proteolytic cleavage by β- and γ- secretases. These enzymes are not the only ones involved in the breakdown of APP: α-secretase cleaves the full-length APP, producing soluble sAPP and, subsequently, p3. Because processing by α-secretase precludes production of full-length Aβ peptides, it is anti-amyloidogenic (Younkin, 1998).. Several lines of evidence suggest that deposition of Aβ-42 is an important initial step in the pathogenesis of Alzheimers disease. Aβ1-42 aggregates more rapidly and is deposited earlier in Alzheimers disease plaques than ...
ALZFORUM | NETWORKING FOR A CURE
Hansson CA, Frykman S, Farmery MR, Tjernberg LO, Nilsberth C, Pursglove SE, Ito A, Winblad B, Cowburn RF, Thyberg J, Ankarcrona M. Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria ...
Alexa Fluor 594 anti-beta-Amyloid 1-16 Antibody anti-B-Amyloid 1-16 - 6E10
|p|Alzheimer's disease is characterized by the accumulation of aggregated Aß peptides in senile plaques and vascular deposits. Aß peptides are derived from amyloid precursor proteins (APP) through sequential proteolytic cleavage of APP by ß- and ?-secretases generating diverse Aß species. Aß can agg
Theres a GSAP for That: Novel APP Partner a New Therapeutic Target? | ALZFORUM
Inhibition of the γ-secretase enzyme that snips amyloid precursor protein (APP) to form Aβ has long been seen as a therapeutic option for Alzheimer disease, but finding a safe, effective inhibitor has proved frustrating. The risk of side effects from γ-secretase inhibition is high, in part because this secretase also cuts Notch, an essential protein for numerous biological functions. The recent cancellation of a high-profile γ-secretase inhibitor clinical trial (see ARF related news story) is the latest disappointment for approaches targeting this secretase. A paper in yesterdays Nature online offers a new tack for this field by reporting the discovery of a γ-secretase activating protein (GSAP) that acts specifically to promote the binding of γ-secretase to APP, but not to Notch. Researchers led by Paul Greengard at the Rockefeller University in New York show that inhibition of GSAP reduces the production of Aβ by 40 to 50 percent both in vitro and in AD model mice, while having no ...
PEN2 Antibody, pAb, Rabbit Antibody - GenScript
Presenilin enhancer protein 2 (PEN2) is a 101-amino acid protein that traverses the membrane twice and it is the regulatory component of the multimeric gamma-secretase complex which also consists of presenilin, APH-1 and Nicastrin. The gamma-secretase complex catalyzes the cleavage of a number of...
Regulated intramembrane proteolysis is certainly a central mobile practice included in | Role of NK1 and NK2 receptors in mouse...
Regulated intramembrane proteolysis is certainly a central mobile practice included in sign membrane layer and transduction proteins turnover. condition of MHCII-containing endosomes, highlighting SPPL2a as a possible medicinal focus on for using up and/or modulating T cells. The concept of intramembrane proteases (I-CLIPs) cleaving within the phospholipid bilayer was originally place forwards structured on digesting of the sterol regulatory elementCbinding proteins (SREBP; Goldstein and Brown, 1997; Kopan and Wolfe, 2004). Generally, I-CLIPs operate as component of a proteolytic series known to as governed intramembrane proteolysis (Split; Lichtenthaler et al., 2011). Intracellular websites (ICDs) of many Split substrates function as signaling elements after their proteolytic discharge as exemplified by the Level path (De Strooper et al., 1999; Freeman and Urban, 2002). Structured on their catalytic middle, serine, metallo, or aspartyl I-CLIPs (Wolfe, 2009) can end up being differentiated. The ...
β-Amyloid 1-42 induces physiological transcriptional regulation of BACE1 | Archivio Istituzionale della Ricerca
The pathogenesis of Alzheimers disease (AD) is only partially understood. β-amyloid (Aβ) is physiologically generated by sequential cleavage of its precursor protein by the β- and the γ-secretase and it is normally disposed of. In Alzheimers disease, Aβ is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant. It has been described a positive feedback loop from the γ- to the β-secretase cleavages of Aβ precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the γ-secretase. These findings show that Aβ precursor protein as well the activity of the γ-secretase are required to obtain the up-regulation of β-secretase which is induced by Presenilin 1 mutations. Then, Aβ 1-42 is the Aβ precursor protein derivative that up-regulates the expression of β-secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation ...
Beta Secretase Substrate (ab101160) | Abcam
Beta Secretase Substrate Functional Assay Kits datasheet (ab101160). Abcam offers quality products including antibodies, assays and other reagents.
Research Grants - 2008
Gamma-secretase is a key enzyme in the development of Alzheimer pathology. It performs the final step in the production of beta-amyloid by cutting beta-amyloid from its parent molecule. Beta-amyloid then goes on to aggregate into amyloid plaques, which are a characteristic feature of Alzheimer pathology. Gamma-secretase also produces other molecules that are important for the normal function of nerve cells.. Like most enzymes, gamma-secretase is localized to specific compartments (microdomains) within cells. Such localization affects the enzymes function by restricting its access to include only proteins that are found in the same compartments. In the case of gamma-secretase, localization is achieved by the attachment of specific fatty acids to different components of the enzyme, thereby determining where those components reside within the cell.. Gopal Thinakaran, Ph.D., and colleagues are studying how localization of gamma-secretase within nerve cells affects the ability of those cells to ...
Reactome | Gamma-secretase complex cleaves mNEXT2
Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.
JEM | The Journal of Experimental Medicine
Liu et al. describe a previously unrecognized cellular complex (∼5 MD) containing β- and γ-secretases that generates a full array of Aβ peptides with physiological Aβ42/40 ratios by sequential cleavages of holo-APP. Such coordinated substrate processing also occurs with the α- and γ-secretases in the RIP mechanism.. ...
β/γ Secretase Antibody Sampler Kit
Glutamate (Metabotropic) Group III Receptors - New β-secretase inhibitors for treatment of Alzheimers disease
APOBEC3 proteins catalyze deamination of cytidines in single-stranded DNA (ssDNA), providing innate protection against retroviral replication by inducing deleterious dC dU hypermutation of replication intermediates. DSB repair, inhibition of APOBEC3G appearance or deaminase activity led to deficient DSB fix, whereas reconstitution of APOBEC3G appearance in leukemia cells improved DSB fix. APOBEC3G activity included digesting of DNA flanking a DSB within an integrated reporter cassette. Atomic power microscopy indicated that APOBEC3G multimers keep company with ssDNA termini, triggering multimer disassembly to multiple catalytic products. These results recognize APOBEC3G being a prosurvival element in lymphoma cells, marking APOBEC3G being a potential focus on for sensitizing lymphoma to rays therapy. Launch Ionizing rays and nearly all anticancer agencies inflict deleterious DNA harm on tumor cells, mostly DNA double-strand breaks (DSBs) and covalent DNA crosslinks. DNA DSBs are extremely ...
AID 71721 - Inhibition of A-beta-42 production by inhibiting Gamma-secretase proteolytic pathway in HEK293 cell stably...
BioAssay record AID 71721 submitted by ChEMBL: Inhibition of A-beta-42 production by inhibiting Gamma-secretase proteolytic pathway in HEK293 cell stably transfected with a double mutant form of human APP(K595N/M596L).
Beta-Secretase 1 ELISA Kits | Biocompare.com
Compare Beta-Secretase 1 ELISA Kits from leading suppliers on Biocompare. View specifications, prices, citations, reviews, and more.
NOMO1 Gene - GeneCards | NOMO1 Protein | NOMO1 Antibody
Complete information for NOMO1 gene (Protein Coding), NODAL Modulator 1, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
JoVE Author Search: Adejare A
Produktübersicht 14 Nicastrin Proteine
Suchen & vergleichen Sie unsere Nicastrin Proteine von vielen Spezies. Finden Sie das richtige Produkt auf antikoerper-online.de.
Search of: dermatofibrosarcoma protuberans - List Results - ClinicalTrials.gov
Maximum-tolerated Dose of Gamma-secretase Inhibitor RO4929097, Defined as the Dose Level Where no More Than 1 Out of 6 Patients Experience DLT at the Highest Dose Level Below the MAD, Graded According to NCI-CTCAE Version 4.0 (Phase Ib ...
Broad Spectrum - Intramembrane Proteolysis
Supplementary MaterialsFigure S1: Kinetic parameter distribution of SNs before evolution. pone.0050905.s003.tif (81K) GUID:?270C2747-8D2C-40C2-A1ED-52BFDFB4C35A Abstract Transmission transduction is the process of routing information inside cells when receiving stimuli from their environment that modulate the behavior and function. In such natural procedures, the receptors, after getting the corresponding indicators, switch on several biomolecules which transduce the sign […]. ...
5??- - Intramembrane Proteolysis
Supplementary MaterialsVideo 1 Time-lapse imaging cells expressing both mt-roGFP and Smac mCherry treated with cisplatin stably. with an indicated medication with 10?nm of TMRM. Live cell imaging was TMP 269 biological activity completed as defined. mmc6.mp4 (20M) GUID:?20E6FE9E-0743-40DF-9A25-5E8A9CEF2F51 TMP 269 biological activity Video 7 EGCG: U2Operating-system cells stably expressing mt-roGFP were stained with TMRM to […]. ...
P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving...
Meredith, J.E.; Thompson, L.A.; Toyn, J.H.; Marcin, L.; Barten, D.M.; Marcinkeviciene, J.; Kopcho, L.; Kim, Y.; Lin, A.; Guss, V.; Burton, C.; Iben, L.; Polson, C.; Cantone, J.; Ford, M.; Drexler, D.; Fiedler, T.; Lentz, K.A.; Grace, J.E.; Kolb, J.; Corsa, J.; Pierdomenico, M.; Jones, K.; Olson, R.E.; Macor, J.E.; Albright, C.F., 2008: P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice
The Rat Central Nervous System Expresses Alzheimers Amyloid Precursor Protein APP<sub>695</sub>, but Not APP<sub>677</sub...
TY - JOUR. T1 - The Rat Central Nervous System Expresses Alzheimers Amyloid Precursor Protein APP695, but Not APP677 (L‐APP Form). AU - Ohgami, Tetsuya. AU - Kitamoto, Tetsuyuki. AU - Tateishi, Jun. PY - 1993/10. Y1 - 1993/10. N2 - Abstract: A novel splicing form of βA4 amyloid precursor protein (APP) lacking exon 15, corresponding to 18 residues, was first reported in leukocytes and then in ubiquitous organs. To determine which APP molecules (APP695, APP751, or APP770) either with (N‐APP) or without (L‐APP; leukocytederived APP) exon 15 were expressed in various organs, we investigated the alternative splicing at exon 15 in the rat brain, kidney, heart, and testis by a PCR analysis of reverse‐transcribed RNA and Southern blot analysis. Regarding APP695 without exons 7 and 8, L‐APP was either seldom or never expressed in the brain, whereas both N‐ and L‐APP were expressed in other organs. On the other hand, regarding APP751/770 containing exon 7, which codes for the Kunitz‐type ...
Purification and aggregation of the amyloid precursor protein intracellular domain<...
TY - JOUR. T1 - Purification and aggregation of the amyloid precursor protein intracellular domain. AU - El Ayadi, Amina. AU - Stieren, Emily S.. AU - Barral, José M.. AU - Oberhauser, Andres F.. AU - Boehning, Darren. PY - 2012/8/28. Y1 - 2012/8/28. N2 - Amyloid precursor protein (APP) is a type I transmembrane protein associated with the pathogenesis of Alzheimers disease (AD). APP is characterized by a large extracellular domain and a short cytosolic domain termed the APP intracellular domain (AICD). During maturation through the secretory pathway, APP can be cleaved by proteases termed α, β, and γ-secretases1. Sequential proteolytic cleavage of APP with β and γ-secretases leads to the production of a small proteolytic peptide, termed Aβ, which is amyloidogenic and the core constituent of senile plaques. The AICD is also liberated from the membrane after secretase processing, and through interactions with Fe65 and Tip60, can translocate to the nucleus to participate in transcription ...
Icaritin, an inhibitor of beta-site amyloid cleaving enzyme-1, inhibits secretion of amyloid precursor protein in APP-PS1...
Background Icaritin (ICT) is a prenylflavonoid derivative from Epimedium brevicornum Maxim. ICT has been shown to have neuroprotective effects. We investigate how ICT affects secretion of amyloid precursor protein (APP). Methods We exposed APP-PS1-HEK293 cells to ICT to investigate its effect on beta-site amyloid cleaving enzyme (BACE)1. Cell viability was evaluated by MTT and lactate dehydrogenase (LDH) assays. The half-maximal inhibitory concentration (IC50) of ICT for BACE1 was measured using fluorescence resonance energy transfer. Effects of ICT on the mRNA expression of APP were assessed by quantitative polymerase chain reaction, and protein expression was measured by western blotting and immunofluorescence. Results Icaritin inhibited BACE1 activity and IC50 was 5.70 ± 1.09 μM. Compared with the control group, at ICT concentrations of 5 μM and 10 μM, the viability increased and LDH leakage decreased in APP-PS1-293 cells. Also, mRNA expression of A disintegrin and metalloproteinase domain
β-Secretase Cleavage of Alzheimers Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE | Science
To address the substrate requirements of BACE-IgG, we designed three peptide substrates, each containing 30 amino acids, extending from P21 to P9 to span the β-secretase cleavage site. These peptides represent: (i) APPwt; (ii) APPsw; and (iii) the MV substitution (P1 changed from Met → Val). In intact cells, endogenous β-secretase cleaves APPsw much better than APPwt, but the MV mutant is not cleaved (22). Pure BACE-IgG cleaves the pure wt peptide with a specific activity of approximately 9 nmol/min/mg, demonstrating that BACE acts as a protease (Fig. 8B). We detect only one cleavage and this is at the correct Asp1 site (24). As expected for β-secretase, the specific activity of BACE-IgG for the Swedish substrate is much higher than for the wt substrate, whereas cleavage of the MV mutant is not detectable at all (Fig. 8B).. Experiments with intact cells suggest that β-secretase has an acidic pH optimum (14, 15). Indeed, a pH titration of BACE activity shows an optimum at pH 4.5 for both ...
APP (Amyloid Precursor Protein), eFluor 570, clone: 22C11, eBioscience™ 100μg; eFluor 570 APP (Amyloid Precursor Protein),...
Featured Papers in 2013 | Alomone Labs
This paper focuses deals with the cleavage of NaVβ2 via BACE-1 (Beta-site APP-cleaving enzyme 1), leading to increased NaV1.1 levels, which do not translocate to the cell plasma membrane. Reinforcing that decreased NaV1.1 levels are involved in AD development/progression. This work cites the use of Alomone Labs Anti-SCN1A (NaV1.1) Antibody (#ASC-001) and Anti-NaVβ2 Antibody (#ASC-007).. The early stages of Alzheimers disease (AD), an incurable neurological affliction with adverse effects on memory and cognition, are often accompanied by aberrant neuronal activity and epileptic seizures - events which are increasingly seen as having a direct influence on ADs progression. Cortical accumulation of amyloid β (Aβ), a peptide derived from amyloid precursor protein (APP), seems to play a prominent role on the onset of AD. Beta-site APP-cleaving enzyme 1 (BACE1) - the rate-determining factor in Aβ synthesis - is significantly high in both AD patients and APP mice (transgenic line with ...
Endosomal entry regulates Notch receptor activation in Drosophila melanogaster | Journal of Cell Biology | Rockefeller...
How could the entry of the Notch receptor into endosomes promote efficient signaling? Because signaling depends on intramembrane cleavage of Notch by γ-secretase, we asked whether altered Notch endosomal transport might affect its cleavage. We directly measured the amount of Notch in endocytic mutant tissue that can be cleaved by γ-secretase by using an assay that induces ligand-independent Notch cleavage in tissue extracts (see Materials and methods). Notch cleavage efficiency ex vivo is measured in Western blots by quantifying the amount of the lower band (corresponding to the γ-secretase cleavage product NICD) relative to the upper band (corresponding to its immediate precursor, the membrane-anchored γ-secretase substrate NEXT) of the ∼120-kD doublet recognized by an antibody against an NICD epitope. As expected, generation of free NICD in this assay is completely blocked by treatment with the γ-secretase inhibitor N-(N-[3,5-difluorophenacetyl-l-alanyl])-S-phenylglycine t-butyl ester ...
Recombinant Human BACE1 His tagged - Labshake
Recombinant Human BACE1 His tagged best suppliers; Recombinant Human BACE1 His tagged best sources; Recombinant Human BACE1 His tagged best vendors; Recombinant Human BACE1 His tagged protocol; Recombinant Human BACE1 His tagged citations; Recombinant Human BACE1 His tagged publications; Recombinant Human BACE1 His tagged papers
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Journal of Alzheimers Disease - Volume 28, issue 3 - Journals - IOS Press
Authors: Moussavi Nik, Seyyed Hani , Wilson, Lachlan , Newman, Morgan , Croft, Kevin , Mori, Trevor A. , Musgrave, Ian , Lardelli, Michael Article Type: Research Article Abstract: Oxygen homeostasis is essential for the development and normal physiology of an organism. Hypoxia causes the mitochondrial electron transport chain to generate higher levels of reactive oxygen species resulting in oxidative stress. Hypoxia can be a direct consequence of hypoperfusion, a common vascular component among Alzheimers disease (AD) risk factors, and may play an important role in AD pathogenesis. Beta-site amyloid-β A4 precursor protein-cleaving enzyme 1 (BACE1) is responsible, with γ-secretase, for cleavage of the amyloid-β protein precursor (AβPP) to produce amyloid-β (Aβ) peptide. A recent study observed that oxidative stress increases BACE1 expression via a regulatory pathway dependent on …γ-secretase cleavage of AβPP and this increases Aβ peptide production. Zebrafish embryos represent normal ...
Galectin 3- binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein<...
TY - JOUR. T1 - Galectin 3- binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein. AU - Seki, Tsuneyoshi. AU - Kanagawa, Motoi. AU - Kobayashi, Kazuhiro. AU - Kowa, Hisatomo. AU - Yahata, Naoki. AU - Maruyama, Kei. AU - Iwata, Nobuhisa. AU - Inoue, Haruhisa. AU - Toda, Tatsushi. N1 - Funding Information: This work was supported by Japan Society for the Promotion of Science (JSPS) Grant 17H06421 (to M. K.) and by CREST (to H. I., N. I., and T. T.). The authors declare that they have no conflicts of interest with the contents of this article. Publisher Copyright: © 2020 Seki et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.. PY - 2020/3/13. Y1 - 2020/3/13. N2 - Alzheimers disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of β-amyloid (Aβ) peptides. Aβ is produced from amyloid precursor protein (APP) that is sequentially cleaved by β- and γ-secretases. ...
Perturbations of the Straight Transmembrane alpha-Helical Structure of the Amyloid Precursor Protein Affect Its Processing by...
Background: Amyloid- neurotoxicity depends on the specificity of the proteolytic cleavage of the amyloid precursor protein (APP) transmembrane domain. Results: The APP transmembrane -helix is straight in a biological membrane bilayer. Conclusion: The flexibility of APP is key for adapting to the lipid environment and modulating proteolytic processing by -secretase. Significance: The dynamic characterization of APP is expected to rationalize the design of -secretase modulators. The amyloid precursor protein (APP) is a widely expressed type I transmembrane (TM) glycoprotein present at the neuronal synapse. The proteolytic cleavage by -secretase of its C-terminal fragment produces amyloid- (A) peptides of different lengths, the deposition of which is an early indicator of Alzheimer disease. At present, there is no consensus on the conformation of the APP-TM domain at the biological membrane. Although structures have been determined by NMR in detergent micelles, their conformation is markedly ...
Michael Willem - Amgen Scholars Program - LMU Munich
The Laboratory for Neurodegenerative Disease Research focuses on the generation of Amyloid ß-peptide (Aß) as the major constituent of neurotoxic amyloid plaques in Alzheimers Disease (AD). Proteolytic processing of an amyloid precursor protein (βAPP) by β- and γ-secretases leads to Aß, whereas βAPP cleavage by α-secretases prevents Aß formation. In order to identify cellular mechanisms involved in the physiological and pathophysiological regulation of AD secretases, the group of Dr. Willem studies the function, expression, subcellular localization and the influence of trafficking and sorting of β- secretase (BACE1) by using transgenic mouse models. Some key topics addressed in the lab regarding the understanding of BACE1 function in physiological and pathophysiological conditions, especially in AD, are:. - Biochemical identification of new proteolytic substrates of the beta-Secretase BACE1. - Immunohistological subcellular localization of compartments in which BACE1 cleaves the ...
Tol2 Gene Trap Integrations in the Zebrafish Amyloid Precursor Protein by Hsin-Kai Liao, Ying Wang et al.
Background-The single spanning transmembrane amyloid precursor protein (APP) and its proteolytic product, amyloid-beta (Aβ) peptide, have been intensely studied due to their role in the pathogenesis of Alzheimers disease. However, the biological role of the secreted ectodomain of APP, which is also generated by proteolytic cleavage, is less well understood. Here, we report Tol2 red fluorescent protein (RFP) transposon gene trap integrations in the zebrafish amyloid precursor protein a (appa) and amyloid precursor-like protein 2 (aplp2) genes. The transposon integrations are predicted to disrupt the appa and aplp2 genes to primarily produce secreted ectodomains of the corresponding proteins that are fused to RFP.
Results-Our results indicate the Appa-RFP and Aplp2 fusion proteins are likely secreted from the central nervous system and accumulate in the embryonic veins independent of blood flow.
Conclusions-The zebrafish appa and aplp2 transposon insertion alleles will be useful for investigating the
beta-Site APP-Cleaving Enzyme 1 (BACE) ELISA Kits
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Beta-site APP-cleaving enzyme 1 isoform C (BACE) polyclonal antibody - Allele Biotech
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Biology and pathophysiology of the amyloid precursor protein | Molecular Neurodegeneration | Full Text
The amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimers disease in large part due to the sequential proteolytic cleavages that result in the generation of β-amyloid peptides (Aβ). Not surprisingly, the biological properties of APP have also been the subject of great interest and intense investigations. Since our 2006 review, the body of literature on APP continues to expand, thereby offering further insights into the biochemical, cellular and functional properties of this interesting molecule. Sophisticated mouse models have been created to allow in vivo examination of cell type-specific functions of APP together with the many functional domains. This review provides an overview and update on our current understanding of the pathobiology of APP.
Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of...
TY - JOUR. T1 - Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688. AU - Ayadi, Amina El. AU - Stieren, Emily S.. AU - Barral, José M.. AU - Boehning, Darren. PY - 2012/8/14. Y1 - 2012/8/14. N2 - The pathogenesis of Alzheimers disease (AD) is associated with proteolytic processing of the amyloid precursor protein (APP) to an amyloidogenic peptide termed Aβ. Although mutations in APP and the secretase enzymes that mediate its processing are known to result in familial forms of AD, the mechanisms underlying the more common sporadic forms of the disease are still unclear. Evidence suggests that the susceptibility of APP to amyloidogenic processing is related to its intracellular localization, and that secretase-independent degradation may prevent the formation of cytotoxic peptide fragments. Recently, single nucleotide polymorphisms in the UBQLN1 gene have been linked to late-onset AD, and its protein product, ...
MAPPING THE TRANSCRIPTIONAL REGULATORY NETWORK OF THE AMYLOID PRECURSOR PROTEIN INTRACELLULAR DOMAIN (AICD) | ScholarBank@NUS
AICD, the C-terminal tail generated from the proteolytic cleavage of the Amyloid Precursor Protein (APP), has been generating interest for its transcriptional modulatory roles. AICD has been hypothesized to have such a function as it is generated by a gamma-secretase-mediated regulated intramembrane proteolysis step, analogous to the generation of Notch intracellular domain (NICD), a well-known transcriptional regulator, from Notch. The AICD/Fe65/Tip60 ternary complex has been proposed as the working transcriptional regulatory complex and some of its target genes have been reported. However, our knowledge of the functions of AICD is still limited due to difficulties in detecting and manipulating the rapidly degraded peptide. Looking at AICD transcription modulation targets from a genome-wide perspective will aid our understanding of the role of AICD tremendously. To this end, AICD chromatin binding sites were investigated from a genome-wide perspective by performing Chromatin Immunoprecipitation ...
Patent US6448229 - Gamma secretase inhibitors - Google Patents
The invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof: wherein X is CH2, O or S. The compounds inhibit gamma secretase without affecting Notch signalling, and hence find use in the treatment or prevention of Alzheimers disease.
Amyloid Precursor Protein
Growth factors are substances that are capable of stimulating cellular proliferation, differentiation, as well as growth. Another probable hypothesis is that the membrane-bound APP may be involved in cell signaling, which is the complex communication system used by cells to govern basic cellular activities and actions. Molecules of APP that are not cleaved by α-secretase are capable of forming internalized endocytic compartments, which in turn are subsequently cleaved by β- and γ- secretases (6). γ- secretase carries out proteolytic modification further by processing the membrane-bound peptide into the amyloid beta (Aβ) peptide form (7). Generation of the Aβ peptide is borne solely from the cleavage of APP in which the amyloid precursor protein intracellular domain (AICD) is released and deposited in aggregated fibrils in senile plaques. Other APP protein family members do not form the Aβ peptide deposits on cleavage (6). It is important to restate that the physiological function of ...
Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors<...
TY - JOUR. T1 - Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors. AU - Miyoshi, Katsue. AU - Ohyagi, Yasumasa. AU - Sakae, Nobutaka. AU - Motomura, Kyoko. AU - Ma, Linqing. AU - Taniwaki, Takayuki. AU - Furuya, Hirokazu. AU - Tabira, Takeshi. AU - Kira, Jun Ichi. PY - 2009. Y1 - 2009. N2 - Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimers disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce overproduction of amyloid-β protein 42. Here, we investigated aberrancy in activation of initiator caspases related to two PS1 gene mutations, I143T and G384A. Acceleration of apoptosis, elevation of caspase-3/7 activity, and significant increases in caspase-4, -8 and -9 activities during apoptosis induced by several agents were found in these mutant PS1-transfected cells. Interestingly, thapsigargin treatment ...
RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing | Translational...
Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimers disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aβ production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel
Increased processing of APLP2 and APP with concomitantformation of APP intracellular domains in BDNF and retinoic acid...
Increased amyloid-β (Aβ) load in the brain, neurite degeneration, neuronal loss, and decreased levels of several neurotrophins are among the characteristics of Alzheimers disease (AD). Generation of Aβ occurs when the amyloid precursor protein (APP) is proteolytically processed by β- and γ-secretases in the amyloidogenic pathway. However, Aβ formation is prevented if APP is cleaved by α- and γ- secretases in the non-amyloidogenic pathway. The normal function of APP is still not fully known. It seems clear that the different fragments that are produced during proteolytic processing have different bioactive properties. APP and its metabolites have been implicated in neurite outgrowth, synaptogenesis, cell adhesion, neuroprotection and apoptosis.. The aim of this thesis was to investigate how neurotrophic factors affect the synthesis and processing of APP and its two mammalian paralogues the APP-like protein-1 and-2 (APLP1 and APLP2). We also wanted to determine how the expression levels ...
Prediction of Memapsin 2 Cleavage Sites - Patent application
0034] Memapsin 2 (BACE1, β-secretase) is a membrane anchored aspartic protease. Although this enzyme is ubiquitously present in many mammalian organs, its functions in the brain are best studied. One of the most important physiological functions of memapsin 2 is the cleavage of a brain membrane protein β-amyloid precursor protein (APP). The hydrolytic product of APP C-terminal fragment is cleaved again by an intramembrane protease γ-secretase to generate a 40- or 42-residue β-amyloid peptide (Ar). Aβ has been shown to feedback down regulate the synaptic activity in neurons (Kamenetz et al., 2003; Lauren et al., 2009). Also, memapsin 2 produced APP N-terminal fragment is involved in the trimming of neurons and axons in the brain (Nikolaev et al., 2009). However, since excess levels of brain Aβ are intimately related to the pathogenesis of Alzheimers disease (Selkoe, 1999), there has been intensive effort to develop inhibitor drugs against memapsin 2 (Ghosh et al., 2008). Important to such ...
Amyloid Precursor Protein (APP) controls excitatory/inhibitory synaptic inputs by regulating the transcriptional activator...
Sequential proteolysis of the amyloid precursor protein (APP) and amyloid-beta petide (Abeta) release is an upstream event in Alzheimers disease (AD) pathogenesis. The function of APP in neuronal physiology is still, however, poorly understood. Along with its paralog APP-like Proteins 1 and 2 (APLP1-2), APP is involved in neurite formation and synaptic function by mechanisms that are not elucidated. APP is a single-pass transmembrane protein expressed at high levels in the brain that resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell interaction processes and/or activation of intracellular pathways of signal transduction. Along this line, the APP intracellular domain (AICD) was reported to act as a transcriptional factor for targeted gene activation that mediates physiological APP functions. Here, we used an unbiased transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and upon ...
Aging | Effects of senescence and angiotensin II on expression and processing of amyloid precursor protein in human cerebral...
The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, β-site APP cleaving enzyme (BACE1) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aβ generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression. Furthermore, Ang II impaired expression of ADAM10 and significantly reduced generation of sAPPα in senescent human BMECs. This inhibitory effect of Ang II was prevented by treatment with BACE1 inhibitor IV. Our results suggest that impairment of α-processing and shift to amyloidogenic pathway of APP contribute to endothelial dysfunction induced by
Plus it
Dementia-Linked Presenilin Mutation Causes Abnormal Splicing. Hirotaka Watanabe, Dan Xia, Takahisa Kanekiyo, Raymond J. Kelleher III, and Jie Shen. (see pages 5085-5096). Presenilin is part of the γ-secretase complex that cleaves amyloid precursor protein (APP) to form β-amyloid (Aβ). Mutations in presenilin cause familial Alzheimers disease (AD) and frontotemporal dementia (FTD), but how such mutations affect γ-secretase function is unclear. Accumulation of Aβ suggests that γ-secretase is overactive in AD, but some presenilin mutations produce FTD without amyloid plaques, suggesting γ-secretase function is diminished. Furthermore, γ-secretase has targets besides APP, notably the signaling molecule Notch, and preventing cleavage of these products-either by reducing γ-secretase activity or by increasing its APP load-might contribute to cognitive impairment in AD and FTD. To address this question, Watanabe et al. created knock-in mice harboring the presenilin mutation c.548G,T, which ...
The Arctic mutation interferes with processing of the amyloid precursor protein
Alzheimers disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by neurofibrillay tangles and deposition of amyloid-β (Aβ) peptides. Several mutations in the gene for amyloid precursor protein (APP) cause familial AD and affect APP processing leading to increased levels of Aβ42. However, the Arctic Alzheimer mutation (APP E693G) reduces Aβ levels. Instead, the increased tendency of Arctic Aβ peptides to form Aβ protofibrils is thought to contribute to the pathogenesis.. In this thesis, the pathogenic mechanisms of the Arctic mutation were further investigated, specifically addressing if and how the mutation affects APP processing. Evidence of a shift towards β-secretase cleavage of Arctic APP was demonstrated. Arctic APP did not appear to be an inferior substrate for α-secretase, but the availability of Arctic APP for α-secretase cleavage was reduced, with diminished levels of cell surface APP in Arctic cells. Interestingly, administration of the ...
Selleck Chemicals Blog-RO4929097 is a small molecule gamma secretase inhibitor
The as yet unfinished story of MPN pathogenesis begun RO4929097 with all the discovery of the JAK2 mutation; afterwards countless other mutations are found in chronic and blast phase of MPN, some involving JAKSTAT signaling activation, many others chromatin remodeling and many others leukemic transformation. Mutations by using a obtain of perform of JAK2, MPL, CBL and these by using a reduction of perform of LNK and NF1 activate the JAKSTAT pathway main to a last phenotype of MPN with alteration of immune response, irritation, angiogenesis, proliferation and resistance to apoptosis. This pathway will be the target of new JAK2 inhibitors. JAK2 mutation, taking place inside of exon 14 of JAK2 and found on 9p24 is the most frequent mutation in MPN, ranging from roughly 96% in PV to 65% in ET and PMF. This mutation has an effect on the auto-inhibitory domain of JAK2 major to constitutive activation of JAK2 and JAK/STAT signaling. In retroviral mouse designs JAK2 confers a PV-like phenotype using a ...
MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model...
Mô tả: Membrane-type 5-matrix metalloproteinase (MT5-MMP) is a proteinase mainly expressed in the nervous system with emerging roles in brain pathophysiology. The implication of MT5-MMP in Alzheimers disease (AD), notably its interplay with the amyloidogenic process, remains elusive. Accordingly, we crossed the genetically engineered 5xFAD mouse model of AD with MT5-MMP-deficient mice and examined the impact of MT5-MMP deficiency in bigenic 5xFAD/MT5-MMP(-/-) mice. At early stages (4 months) of the pathology, the levels of amyloid beta peptide (Aβ) and its amyloid precursor protein (APP) C-terminal fragment C99 were largely reduced in the cortex and hippocampus of 5xFAD/MT5-MMP(-/-), compared to 5xFAD mice. Reduced amyloidosis in bigenic mice was concomitant with decreased glial reactivity and interleukin-1β (IL-1β) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of α-, β- and γ-secretases. The positive impact of... ...
Niina Koistinen, licentiatseminarium - Institutionen för neurokemi
The amyloid precursor protein (APP) protein has been in the limelight of research on Alzheimer´s disease (AD) pathogenesis because its proteolytic processing gives rise to the neurotoxic amyloid β (Aβ) peptide, the main constituent of amyloid plaques in the brains of AD patients. APP is sequentially processed by at least three different proteases termed α-, β-, and γ-secretases. The proteolytic processing of APP can be divided into two different pathways, the non-amyloidogenic and the amyloidogenic. Whether APP is processed by the non-amyloidogenic or the amyloidogenic pathway is highly dependent on co-localization of APP with the different processing enzymes. Hence, understanding the mechanism underlying regulation of APP trafficking and its related secretases is of great importance in our understanding of AD and AD pathogenesis. The aim of this thesis was to study the processing and trafficking of APP, how it may be regulated by the interaction with the adaptor protein, Fe65, and by a ...
LY-411575 | γ-secretase Inhibitor | MedChemExpress
LY-411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), and also inhibits Notch S3 cleavage with IC50 of 0.39 nM. - Mechanism of Action & Protocol.
eCite - Identification of heparin-binding domains in the amyloid precursor protein of Alzheimers disease by deletion...
Identification of heparin-binding domains in the amyloid precursor protein of Alzheimers disease by deletion mutagenesis and peptide mapping
RO 4929097 | γ-Secretase inhibitor | RO4929097 | CAS [847925-91-1] | Axon 2521 | Axon Ligand™ with |98% purity available from...
RO 4929097 | γ-Secretase inhibitor | RO4929097 | CAS [847925-91-1] | Axon 2521 | Axon Ligand™ with >98% purity available from supplier Axon Medchem, prime source of life science reagents for your research
OriGene - BACE1 (NM 012104) cDNA Clone
BACE1 - BACE1 (untagged)-Human beta-site APP-cleaving enzyme 1 (BACE1), transcript variant a available for purchase from OriGene - Your Gene Company.
NOTCH 2 Antibody 100-401-408
Anti-Notch 2 Antibody recognizes Notch 2 that is synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase (S1 cleavage) in the trans-golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved (S2 cleavage) by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin-dependent gamma-secretase (S3 cleavage) to release the intracellular domain (NICD) from the membrane.
The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses.
Exclusive to Global Medical Discovery (new Significance Statement and new figure). The role of metalloproteinase ADAM17 in regulating
ADAM10 - Disintegrin and metalloproteinase domain-containing protein 10 precursor - Bos taurus (Bovine) - ADAM10 gene & protein
Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (By similarity). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:10097139). Contributes to the normal cleavage of the cellular prion protein (By similarity). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (By similarity). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (By similarity). Also cleaves the ectodomain of the
GSI - Publications 2012 to 2014
Proceedings of the International Symposium, EXON, VladivostokVladivostok, Russia, 1 Oct 2012 - 6 Oct 20122012-10-012012-10-06 New Jersey : WORLD SCIENTIFIC 263 - 272 (2013) [10.1142/9789814508865_0036]2013 BibTeX , EndNote: XML, Text , RIS http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article Kienle, P. (Gefeierter) ; Bosch, F. (Corresponding author)GSI* ; Bühler, P. ; Faestermann, T. ; Litvinov, Y.GSI* ; Winckler, N.GSI* ; Sanjari, M. S.GSI* ; Shubina, D.GSI* ; Atanasov, D.GSI* ; Geissel, H.GSI* ; Ivanova, V.GSI* ; Yan, X. L. ; Boutin, D.GSI* ; Brandau, C.GSI* ; Dillmann, I.GSI* ; Dimopoulou, C.GSI* ; Heß, R.GSI* ; Hillenbrand, P.-M.GSI* ; Izumikawa, T. ; Knöbel, R.GSI* ; Kurcewicz, J.GSI* ; Kuzminchuk, N. ; Lestinsky, M.GSI* ; Litvinov, S.GSI* ; Ma, X. W. ; Maier, L. ; Mazzocco, M.GSI* ; Mukha, I.GSI* ; Nociforo, C.GSI* ; Nolden, F.GSI* ; Scheidenberger, C.GSI* ; Spillmann, U.GSI* ; Steck, M.GSI* ; Stöhlker, T.GSI* ; Sun, B. H. ; Suzaki, F. ; Torilov, S. Y. ...
5HDX | BACE-1 IN COMPLEX WITH (7AR)-7A-(5-CYANOTHIOPHEN-2-YL)-6-(4-ETHOXY-5- FLUORO-6-METHYLPYRIMIDIN-2-YL)-3-METHYL-4...
cansSAR 3D Structure of 5HDX | BACE-1 IN COMPLEX WITH (7AR)-7A-(5-CYANOTHIOPHEN-2-YL)-6-(4-ETHOXY-5- FLUORO-6-METHYLPYRIMIDIN-2-YL)-3-METHYL-4-OXOOCTAHYDRO-2H-PYRROLO[3, 4-D]PYRIMIDIN-2-IMINIUM | 5HDX_A | Beta-secretase 1 - Also known as BACE1_HUMAN, BACE1, BACE, KIAA1149. Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase (PubMed:10656250, PubMed:10677483, PubMed:20354142). Cleaves CHL1 (By similarity). Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3 (via their VHS domain); the interaction highly increases when BACE1 is phosphorylated at Ser-498 (PubMed:14567678, PubMed:15886016). Interacts with RTN3 and RTN4 (PubMed:15286784, PubMed:16965550, PubMed:16979658). Interacts with SNX6 (PubMed
Up-Regulation of Cyclooxygenase-2 Expression Is Involved in R(+)-Methanandamide-Induced Apoptotic Death of Human Neuroglioma...
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From Alzheimer to Huntington: why is a structural understanding so difficult? | The EMBO Journal
While predisposition to AD has been linked to mutations of several genes, including those of presenilins and apolipoprotein E, mainly two protein components are present in the two types of AD aggregates (reviewed in Hardy and Selkoe, 2002). Plaques are generated by deposition of the amyloid peptides (Aβ), which are degradation products of the amyloid precursor protein (APP). APP is a transmembrane cell surface glycoprotein, expressed in five isoforms, with APP(695) being the dominant isoform in brain. APP can be cleaved by three different proteases, called α, β and γ secretases. When APP is concomitantly hydrolysed by β‐secretase at the N‐terminus of Aβ and by the γ‐secretase within the membrane (Lichtenthaler et al., 2002), the two main products, Aβ(1-40) and Aβ(1-42), migrate outside the cell and give rise to fibrils. When APP is cut by α‐secretase, the resulting soluble peptides are generally considered non‐toxic, although a recent report shows that the p3 peptide derived ...
Presenilin Links Alzheimers Disease and Stress | Science Signaling
Presenilin 1 (PS1) is a transmembrane protein localized to internal cell membranes and is involved in processing amyloid β precursor protein to produce Aβ (a protein implicated in Alzheimers disease) and processing of Notch (a signaling protein involved in development). Kim et al. show that overexpression of PS1 in embryonic kidney cells or neuroblastoma cells inhibits activation of the stress-activated protein kinase (SAPK) pathway and suppresses peroxide-induced apoptosis. Experiments in which PS1 and constitutively active mutants of the proteins in the SAPK pathway were coexpressed indicate that PS1 exerts its inhibitory effect upstream of the guanosine triphosphatase Rac1 or via a Rac1-independent pathway. PS1-deficient mouse embryo fibroblasts exhibited enhanced SAPK activity under resting conditions and increased apoptosis upon treatment with peroxide. The γ-secretase activity of PS1 was determined to be essential for the inhibition of SAPK signaling based on analysis of various PS1 ...
Beta-secretase enzyme compositions and methods - Elan Pharmaceuticals, Inc.
Disclosed are various forms of an active, isolated β-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the
Whats hot today: Current papers in developmental biology and gene function
The aggregation of the amyloid-β (Aβ; see Drosophila Appl) peptide into fibrillar deposits has long been considered the key neuropathological hallmark of Alzheimers disease (AD). Aβ peptides are generated from proteolytic processing of the transmembrane Aβ precursor protein (AβPP) via sequential proteolysis through the β-secretase activity of β-site AβPP-cleaving enzyme (BACE1) and by the intramembranous enzyme γ-secretase. For over a decade, Drosophila melanogaster has been used as a model organism to study AD, and two different approaches have been developed to investigate the toxicity caused by AD-associated gene products in vivo. In one model, the Aβ peptide is directly over-expressed fused to a signal peptide, allowing secretion of the peptide into the extracellular space. In the other model, human AβPP is co-expressed with human BACE1, resulting in production of the Aβ peptide through the processing of AβPP by BACE1 and by endogenous fly γ-secretase. This study consisted of ...
Dictyostelium possesses highly diverged presenilin/γ-secretase that regulates growth and cell-fate specification and can...
Fig. 3. Dictyostelium has PS-dependent γ-secretase activity that processes human APP to release Aβ peptides. (A) Diagrams of human APP α, β and γ proteolytic cleavage sites, and processed fragments; shown are FL (full-length), ΔN (N-terminal deletion), α- and β-CTFs, Aβ40 peptide, and AICD regions. (B) Media conditioned by growing WT and ps1-null cells that express ΔN-APP (a truncated human APP) were analyzed for levels of Aβ40 and Aβ42 peptides by quantitative ELISA. Fresh media and media conditioned by native WT cells were used as negative controls. Bars indicate standard errors that are derived from two independent experiments, each with two replicates. (C)Protein samples were collected from growing native WT Dictyostelium, or WT and ps1-null Dictyostelium that express ΔN-APP. ΔN-APP expression and processed fragments (arrows) were determined by immunoblot assay using α-APP C-terminus. (D) Protein samples were collected from native and APP-expressing CHO cells untreated or ...