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  • 1
    Book
    Book
    Bentham Science Publishers Ltd.
    Language: English
    Keywords: Amyloid- Peptide (A) Alzheimer'S Disease (Ad) Protection A42 Aggregation A40 Nmr Heat Shock Protein L-Pgds Heme Methionine Oxidation Neprilysin (Nep) Insulin Degrading Enzyme (Ide) Matrix Metalloprotease (Mmp) Adam10 Sirt1.
    Source: Bentham Science Publishers
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e32568
    Description: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. ; In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different co-incubation experiments were performed with competing ligands of the respective receptor. ; This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier.
    Keywords: Research Article ; Biology ; Materials Science ; Medicine ; Biotechnology ; Pharmacology ; Biochemistry
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Cellular and Molecular Life Sciences (CMLS), Jan, 2013, Vol.70(1), p.309(25)
    Description: Byline: Tamara Jefferson (1), Ulrich Keller (2,3), Caroline Bellac (3), Verena V. Metz (4), Claudia Broder (1), Jana Hedrich (5), Anke Ohler (6), Wladislaw Maier (7), Viktor Magdolen (8), Erwin Sterchi (9), Judith S. Bond (10), Arumugam Jayakumar (11), Heiko Traupe (12), Athena Chalaris (1), Stefan Rose-John (1), Claus U. Pietrzik (7), Rolf Postina (4), Christopher M. Overall (3), Christoph Becker-Pauly (1,13) Keywords: Meprin; ADAM10; Metalloproteases; Proteomics; TAILS; Degradome Abstract: The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin [alpha] and [beta] we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)--the constitutive [alpha]-secretase--is activated by meprin [beta] through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin [beta], this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin.sup.-/- mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes. Author Affiliation: (1) Institute of Biochemistry, Christian-Albrechts-University, 24118, Kiel, Germany (2) Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich, ETH Hoenggerberg, HPM D24, Zurich, Switzerland (3) Departments of Oral Biological and Medical Sciences and Biochemistry and Molecular Biology, Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada (4) Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany (5) Institute of Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany (6) Cell and Matrix Biology, Johannes Gutenberg University, Mainz, Germany (7) Institute of Pathobiochemistry, University Medical Center, Johannes Gutenberg-University, Mainz, Germany (8) Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany (9) Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland (10) Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA (11) Department of Experimental Therapeutics, M.D. Anderson Cancer Center, The University of Texas, Houston, TX, USA (12) Department of Dermatology, University Hospital Munster, Munster, Germany (13) Unit for Degradomics of the Protease Web, Christian-Albrechts-University, Rudolf-Hober-Str. 1, 24118, Kiel, Germany Article History: Registration Date: 23/07/2012 Received Date: 17/04/2012 Accepted Date: 23/07/2012 Online Date: 01/09/2012 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00018-012-1106-2) contains supplementary material, which is available to authorized users.
    Keywords: Peptides -- Analysis ; Medical Schools -- Analysis ; Proteases -- Analysis ; Drugstores -- Analysis
    ISSN: 1420-682X
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  • 4
    Language: English
    In: Molecular neurodegeneration, 17 July 2013, Vol.8, pp.25
    Description: The N-methyl-D-aspartate receptors are key mediators of excitatory transmission and are implicated in many forms of synaptic plasticity. These receptors are heterotetrameres consisting of two obligatory NR1 and two regulatory subunits, usually NR2A or NR2B. The NR2B subunits are abundant in the early postnatal brain, while the NR2A/NR2B ratio increases during early postnatal development. This shift is driven by NMDA receptor activity. A functional interplay of the Low Density Lipoprotein Receptor Related Protein 1 (LRP1) NMDA receptor has already been reported. Such abilities as interaction of LRP1 with NMDA receptor subunits or its important role in tPa-mediated NMDA receptor signaling were already demonstrated. Moreover, mice harboring a conditional neuronal knock-out mutation of the entire Lrp1 gene display NMDA-associated behavioral changes. However, the exact role of LRP1 on NMDA receptor function remains still elusive. To provide a mechanistic explanation for such effects we investigated whether an inactivating knock-in mutation into the NPxY2 motif of LRP1 might influence the cell surface expression of LRP1 and NMDA receptors in primary cortical neurons. Here we demonstrate that a knock-in into the NPxY2 motif of LRP1 results in an increased surface expression of LRP1 and NR2B NMDA receptor subunit due to reduced endocytosis rates of LRP1 and the NR2B subunit in primary neurons derived from LRP1ΔNPxY2 animals. Furthermore, we demonstrate an altered phosphorylation pattern of S1480 and Y1472 in the NR2B subunit at the surface of LRP1ΔNPxY2 neurons, while the respective kinases Fyn and casein kinase II are not differently regulated compared with wild type controls. Performing co-immunoprecipitation experiments we demonstrate that binding of LRP1 to NR2B might be linked by PSD95, is phosphorylation dependent and this regulation mechanism is impaired in LRP1ΔNPxY2 neurons. Finally, we demonstrate hyperactivity and changes in spatial and reversal learning in LRP1ΔNPxY2 mice, confirming the mechanistic interaction in a physiological readout. In summary, our data demonstrate that LRP1 plays a critical role in the regulation of NR2B expression at the cell surface and may provide a mechanistic explanation for the behavioral abnormalities detected in neuronal LRP1 knock-out animals reported earlier.
    Keywords: Neurons -- Metabolism ; Receptors, LDL -- Metabolism ; Receptors, N-Methyl-D-Aspartate -- Metabolism ; Tumor Suppressor Proteins -- Metabolism
    E-ISSN: 1750-1326
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  • 5
    Language: English
    In: Advances in Alzheimer Research, pp.205-233
    Description: The LDL-receptor gene family constitutes a class of structurally closely related cell surface receptors fulfilling diverse functions in different organs, tissues, and cell types. The LDL-receptor is the prototype of this family, which also includes the VLDLR, ApoER2/LRP8, LRP1 and LRP1B, as well as Megalin/GP330, SorLA-1/LR11, LRP5, LRP6 and MEGF7. Recently several lines of evidence have positioned the LDL receptor gene family as one of the key players in Alzheimer's disease (AD) research. Initially this receptor family was of high interest due to its key function in cholesterol/apolipoprotein E (ApoE) uptake, with the ε4 allele of ApoE as the strongest genetic risk factor for late-onset AD. It has been established that the cholesterol metabolism of the cell has a strong impact on the production of Aβ, the major component of the plaques found in the brain of AD-patients. The original report that soluble amyloid precursor protein (APP) containing the kunitz proteinase inhibitor (KPI) domain might act as a ligand for LRP1 led to a complex investigation of the interaction of both proteins and their potential function in AD development. Meanwhile, it has been demonstrated that LRP1 might bind to APP independent of the KPI domain in APP. This APP - LRP1 interaction is facilitated through a trimeric complex of APP-FE65-LRP1, which has a functional role in APP processing. Along with LRP1, APP is transported from the early secretory compartments to the cell surface and subsequently internalised into the endosomal / lysosomal compartments. Recent investigations indicate that VLDLR, ApoER2 and SorLA fulfil a similar role in shifting APP localisation in the cell, which affects APP processing and the production of the APP derived Amyloid β-peptide (Aβ). In addition to the effect of lipoprotein receptors on APP processing and Aβ production, LRP1 has been shown to bind Aβ directly or indirectly through Aβ-lactoferrin, Aβ-α2M and Aβ-ApoE complexes in vitro and in vivo. Therefore based on these observations two LRP1 mediated clearance mechanisms of Aβ are proposed to play a crucial role in the prevention of AD: either Aβ-uptake into a cell with its subsequent degradation or its transport out of the brain over the blood brain barrier into the periphery. Following this export Aβ is degraded in the liver, where LRP1 potentially conducts the removal of Aβ from the blood stream. Although the involvement of LDL-R-family members in AD is not yet fully understood it becomes clear that they can directly affect APP production, Aβ-clearance and Aβ-transport over the blood brain barrier as well as NMDA receptor function.
    Keywords: Ldl Receptor Family ; Alzheimer'S Disease ; Blood-Brain-Barrier ; Apoe ; Apoe4 ; Amyloid Precursor Protein ; Fe65 ; Vldl Receptor ; Lrp1 ; Sorla ; Rage ; Apoe2 Receptor ; Cholesterol ; Shedding ; Amyloid Beta A ; A Clearance ; Npxy Motif ; Bace ; Gamma-Secretase.
    Source: Bentham Science Publishers
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  • 6
    Language: English
    In: Cellular and Molecular Life Sciences, 2013, Vol.70(2), pp.309-333
    Description: The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin −/− mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes.
    Keywords: Meprin ; ADAM10 ; Metalloproteases ; Proteomics ; TAILS ; Degradome
    ISSN: 1420-682X
    E-ISSN: 1420-9071
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  • 7
    Language: English
    In: The Journal of biological chemistry, 05 August 2011, Vol.286(31), pp.27741-50
    Description: Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin β is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin β and the amyloid precursor protein (APP). Although APP is intensively studied as a ubiquitously expressed cell surface protein, which is involved in Alzheimer disease, its precise physiological role and relevance remain elusive. Based on a novel proteomics technique termed terminal amine isotopic labeling of substrates (TAILS), APP was identified as a substrate for meprin β. Processing of APP by meprin β was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin β(-/-) mouse brain lysates. Although these APP fragments were in the range of those responsible for caspase-induced neurodegeneration, we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin β is a physiologically relevant enzyme in APP processing.
    Keywords: Amyloid Beta-Protein Precursor -- Metabolism ; Tiopronin -- Metabolism
    E-ISSN: 1083-351X
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