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  • 1
    Language: English
    In: Experimental brain research, April 2012, Vol.217(3-4), pp.325-9
    Description: Byline: Ulrike C. Muller (1), Claus U. Pietrzik (2), Thomas Deller (3) Author Affiliation: (1) Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany (2) Institute of Pathobiochemistry, Molecular Neurodegeneration, University Medical Center, Johannes Gutenberg-University Mainz, 55099, Mainz, Germany (3) Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany Article History: Registration Date: 10/02/2012 Online Date: 19/02/2012
    Keywords: Amyloid Beta-Peptides -- Physiology ; Amyloid Beta-Protein Precursor -- Physiology ; Brain -- Physiology
    ISSN: 00144819
    E-ISSN: 1432-1106
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  • 2
    Language: English
    In: Experimental Brain Research, 2012, Vol.217(3), pp.377-387
    Description: In this review, we will primarily focus on the role of members of the low-density lipoprotein receptor (LDL-R) family that are involved in trafficking and processing of the amyloid precursor protein (APP). We will discuss the role of the LDL-receptor family members, low-density lipoprotein receptor-related protein 1 (LRP1), LRP1b, apolipoprotein E receptor 2, sortilin-related receptor (SorLA/LR11) and megalin/LRP2 on the physiological function of APP and its cellular localization. Additionally, we will focus on adaptor proteins that have been shown to influence the physiological function of LDL-R family members in combination with APP processing. The results in this review emphasize that the physiological function of APP cannot be explained by the focus on the APP protein alone but rather in combination with various direct or indirect interaction partners within the cellular environment.
    Keywords: Low-density lipoprotein receptor (LDL-R) family ; Low-density lipoprotein receptor-related protein 1 (LRP1) ; LRP1b ; ApoER2 ; SorLA/LR11 ; Amyloid precursor protein (APP)
    ISSN: 0014-4819
    E-ISSN: 1432-1106
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  • 3
    Language: English
    In: Pharmaceutical Research, 2017, Vol.34(12), pp.2637-2651
    Description: The accumulation of the neurotoxin beta-amyloid (Aβ) is a major hallmark in Alzheimer’s disease (AD). Aβ homeostasis in the brain is governed by its production and various clearance mechanisms. Both pathways are influenced by the ubiquitously expressed low-density lipoprotein receptor-related protein 1 (LRP1). In cerebral blood vessels, LRP1 is an important mediator for the rapid removal of Aβ from brain via transport across the blood-brain barrier (BBB). Here, we summarize recent findings on LRP1 function and discuss the targeting of LRP1 as a modulator for AD pathology and drug delivery into the brain.
    Keywords: Alzheimer's disease ; angiopeps ; beta-amyloid ; blood-brain barrier ; choroid plexus ; drug delivery ; LRP1 ; targeting
    ISSN: 0724-8741
    E-ISSN: 1573-904X
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  • 4
    Language: English
    In: PLoS ONE, 2012, Vol.7(1), p.e30484
    Description: The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC 50 of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex.
    Keywords: Research Article ; Biology ; Chemistry ; Medicine ; Chemistry ; Neurological Disorders ; Biochemistry
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Cellular and molecular life sciences : CMLS, April 2012, Vol.69(8), pp.1353-75
    Description: The amyloid precursor protein (APP) is part of a larger gene family, which has been found to form homo- or heterotypic complexes with its homologues, whereby the exact molecular mechanism and origin of dimer formation remains elusive. In order to assess the cellular location of dimerization, we have generated a cell culture model system in CHO-K1 cells, stably expressing human APP, harboring dilysine-based organelle sorting motifs [KKAA-endoplasmic reticulum (ER); KKFF-Golgi], accomplishing retention within early secretory compartments. We show that APP exists as disulfide-bonded dimers upon ER retention after it was isolated from cells, and analyzed by SDS-polyacrylamide gel electrophoresis under non-reducing conditions. In contrast, strong denaturing and reducing conditions, or deletion of the E1 domain, resulted in the disappearance of those dimers. Thus we provide first evidence that a fraction of APP can associate via intermolecular disulfide bonds, likely generated between cysteines located in the extracellular E1 domain. We particularly visualize APP dimerization itself and identified the ER as subcellular compartment of its origin using biochemical or split GFP approaches. Interestingly, we also found that minor amounts of SDS-resistant APP dimers were located to the cell surface, revealing that once generated in the oxidative environment of the ER, dimers remained stably associated during transport. In addition, we show that APP isoforms encompassing the Kunitz-type protease inhibitor (KPI) domain exhibit a strongly reduced ability to form cis-directed dimers in the ER, whereas trans-mediated cell aggregation of Drosophila Schneider S2-cells was isoform independent. Thus, suggesting that steric properties of KPI-APP might be the cause for weaker cis-interaction in the ER, compared to APP695. Finally, we provide evidence that APP/APLP1 heterointeractions are likewise initiated in the ER.
    Keywords: Amyloid Beta-Protein Precursor -- Metabolism ; Endoplasmic Reticulum -- Metabolism ; Protein Isoforms -- Metabolism
    ISSN: 1420682X
    E-ISSN: 1420-9071
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  • 6
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, August 2015, Vol.29(8), pp.3549-57
    Description: The meprin β metalloproteinase is an important enzyme in extracellular matrix turnover, inflammation, and neurodegeneration in humans and mice. Previous studies showed a diminished cleavage of certain meprin β substrates in the presence of calcium, although the mechanism was not clear. With the help of a specific fluorogenic peptide assay and the human amyloid precursor protein as substrate, we demonstrated that the influence of calcium is most likely a direct effect on human meprin β itself. Analyzing the crystal structures of pro- and mature meprin β helped to identify a cluster of negatively charged amino acids forming a potential calcium binding site. Mutation of 2 of these residues (D204A and D245A) led to severe differences in proteolytic activity and cellular localization of meprin β. D245A was almost completely inactive and largely stored into intracellular vesicles, indicating severe misfolding of the protein. Astonishingly, D204A was not transported to the cell surface, but exhibited strong β-secretase activity, resulting in massive accumulation of Aβ-peptides. This could be explained by constitutive maturation of this meprin β mutant already in the early secretory pathway. We hypothesize that lacking D204 abrogates the capability of binding calcium in the catalytic domain, an important step for proper folding of the propeptide and subsequent inhibition of the protease. This is supported by the inhibition constant of calcium for meprin β (inhibitory constant 50 = 11 mM), which resembles the physiologic concentrations found in the endoplasmic reticulum. For instance, it was shown for amyotrophic lateral sclerosis that a loss of calcium in the endoplasmic reticulum leads to the misfolding of calcium-dependent proteins, which might also be relevant for proper function of meprin β.
    Keywords: App ; Amyloid Β ; Protease ; Protein Folding ; Calcium -- Metabolism ; Metalloendopeptidases -- Metabolism
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 7
    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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  • 8
    Language: English
    In: Cellular and Molecular Life Sciences, 2010, Vol.67(1), pp.135-145
    Description: The proximal NPXY and distal NPXYXXL motifs in the intracellular domain of LRP1 play an important role in regulation of the function of the receptor. The impact of single and double inactivating knock-in mutations of these motifs on receptor maturation, cell surface expression, and ligand internalization was analyzed in mutant and control wild-type mice and MEFs. Single inactivation of the proximal NPXY or in combination with inactivation of the distal NPXYXXL motif are both shown to be associated with an impaired maturation and premature proteasomal degradation of full-length LRP1. Therefore, only a small mature LRP1 pool is able to reach the cell surface resulting indirectly in severe impairment of ligand internalization. Single inactivation of the NPXYXXL motif revealed normal maturation, but direct impairment of ligand internalization. In conclusion, the proximal NPXY motif proves to be essential for early steps in the LRP1 biosynthesis, whereas NPXYXXL appears rather relevant for internalization.
    Keywords: Internalization motif ; LRP1 ; Endocytosis ; Maturation ; NPXY motif ; Proteasomal degradation ; Intracellular domain ; Lipoprotein receptor
    ISSN: 1420-682X
    E-ISSN: 1420-9071
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(3), p.e92068
    Description: This study was performed to explore the feasibility of tracing nanoparticles for drug transport in the healthy rat brain with a clinical MRI scanner. Phantom studies were performed to assess the R1 ( =  1/T1) relaxivity of different magnetically labeled nanoparticle (MLNP) formulations that...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    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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