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Dive into the research topics where Andrea Rittger is active.

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Featured researches published by Andrea Rittger.


Experimental Brain Research | 2012

Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and Presenilin

Johannes Prox; Andrea Rittger; Paul Saftig

Alzheimers disease causing mutations in the amyloid precursor protein (APP) or in the Presenilin 1 (PS1) or Presenilin 2 (PS2) genes increase the production of amyloid peptides (Aβ) that precipitate in amyloid plaques. Since amyloid plaques are also a prominent feature of sporadic Alzheimers disease (AD), abnormal proteolysis of APP and the generation of amyloid beta (Aβ) are key events in the pathogenesis of AD. The proteases (secretases) that cleave APP are therefore important therapeutic targets, both for the rare familial forms but likely also for the sporadic forms of AD. The identification and understanding of the (neuro)biological functions of the α-, β-, and presenilin/γ-secretase (complexes) is important for the development of drugs and the delineation of their associated side effects. The potential impact of this type of research exceeds the AD field since the function of these secretases are also linked to cellular pathways like ectodomain shedding of growth factors and regulated intramembrane proteolysis of receptors in developmental biology, tissue homeostasis, and tumorigenesis. The generation of mice deficient in presenilin 1, presenilin 2, the α-secretase ADAM10, and the β-secretases BACE1 and BACE2 were instrumental for the elucidation of the physiological functions of these proteases. Using these mouse models understanding how these secretases regulate amyloid peptide formation and how they exert their diverse biological functions could be significantly increased. This review attempts to summarize selected aspects of the current view of the multiple roles such proteases play in health and disease.


Biology of Reproduction | 2008

Regulated Expression of ADAM8 (a Disintegrin and Metalloprotease Domain 8) in the Mouse Ovary: Evidence for a Regulatory Role of Luteinizing Hormone, Progesterone Receptor, and Epidermal Growth Factor-Like Growth Factors

Venkataraman Sriraman; Ursula Eichenlaub-Ritter; Joerg W. Bartsch; Andrea Rittger; Sabine M. Mulders; JoAnne S. Richards

ADAM8 (a disintegrin and metalloprotease domain 8) is expressed in immune, neuronal, and bone progenitor cells and is thought to be involved in the tissue-remodeling process. Microarray analyses indicate that Adam8 is a potential target of the progesterone receptor (Pgr) in murine ovary. Further studies document that Adam8 mRNA and protein are expressed in granulosa cells and cumulus cells of periovulatory follicles whereas expression is significantly reduced in Pgr null mice that fail to ovulate. There is a reduced expression in granulosa cells from cultured, in vitro ovulated follicles exposed to inhibitors of progesterone or epidermal growth factor signaling while epiregulin induced its expression in the absence of hCG. In vitro studies with primary mouse granulosa cells document that Adam8 is induced in response to forskolin (Fo) and phorbol ester (PMA) or Fo and Amphiregulin treatment. To understand the transcriptional regulation of the Adam8, we amplified 1 kb of the mouse Adam8 promoter by PCR and subcloned it into a pGL3-luciferase reporter construct. The Adam8 promoter-luciferase constructs are induced by Fo and PMA treatment after transfection into rat granulosa cells, and cotransfection with a PGR-A expression vector further augment basal and Fo/PMA inducibility. Site-specific mutations within the -615/+50 promoter document that a GC-rich region, NF-1 (nuclear factor-1) site, and putative TATA box are critical for Adam8 promoter activation by Fo/PMA. Thus, ADAM8 is expressed in a stage-specific manner and is hormonally regulated in ovulating follicles by the coordinate actions of LH and PGR. To our knowledge, ADAM8 is the first member of the ADAM family shown to be hormonally regulated.


Neurobiology of Disease | 2009

Non-proteolytic effect of β-site APP-cleaving enzyme 1 (BACE1) on sodium channel function

Tobias Huth; Karoline Schmidt-Neuenfeldt; Andrea Rittger; Paul Saftig; Karina Reiss; Christian Alzheimer

The beta-site APP-cleaving enzyme 1 (BACE1) is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimers disease. Here, we elaborate on the recent finding that auxiliary subunits of voltage-gated sodium channels (beta2 and beta4) are BACE substrates. BACE1 produced complex effects on sodium channel gating that could be only partially explained by beta2/beta4 cleavage. To characterize the unexpected non-proteolytic effect of BACE1, we examined HEK cells co-transfected with only Nav1.2 and either normal or catalytically inactive BACE1. Both BACE1 variants produced virtually identical effects on sodium channel gating, which would lead to enhanced cellular excitability. The non-proteolytic BACE1 effect on Nav1.2 current was confirmed in murine neuroblastoma cells, which express sodium channels endogenously, but lack beta2 and beta4. Our study reveals an important facet of BACE1 function that should help to decipher the role of BACE1 in normal and demented brain.


Pflügers Archiv: European Journal of Physiology | 2011

β-Site APP-cleaving enzyme 1 (BACE1) cleaves cerebellar Na+ channel β4-subunit and promotes Purkinje cell firing by slowing the decay of resurgent Na+ current

Tobias Huth; Andrea Rittger; Paul Saftig; Christian Alzheimer

In cerebellar Purkinje cells, the β4-subunit of voltage-dependent Na+ channels has been proposed to serve as an open-channel blocker giving rise to a “resurgent” Na+ current (INaR) upon membrane repolarization. Notably, the β4-subunit was recently identified as a novel substrate of the β-secretase, BACE1, a key enzyme of the amyloidogenic pathway in Alzheimers disease. Here, we asked whether BACE1-mediated cleavage of β4-subunit has an impact on INaR and, consequently, on the firing properties of Purkinje cells. In cerebellar tissue of BACE1−/− mice, mRNA levels of Na+ channel α-subunits 1.1, 1.2, and 1.6 and of β-subunits 1–4 remained unchanged, but processing of β4 peptide was profoundly altered. Patch-clamp recordings from acutely isolated Purkinje cells of BACE1−/− and WT mice did not reveal any differences in steady-state properties and in current densities of transient, persistent, and resurgent Na+ currents. However, INaR was found to decay significantly faster in BACE1-deficient Purkinje cells than in WT cells. In modeling studies, the altered time course of INaR decay could be replicated when we decreased the efficiency of open-channel block. In current-clamp recordings, BACE1−/− Purkinje cells displayed lower spontaneous firing rate than normal cells. Computer simulations supported the hypothesis that the accelerated decay kinetics of INaR are responsible for the slower firing rate. Our study elucidates a novel function of BACE1 in the regulation of neuronal excitability that serves to tune the firing pattern of Purkinje cells and presumably other neurons endowed with INaR.


Gut | 2013

Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice

Christian Sina; Simone Lipinski; Olga Gavrilova; Konrad Aden; Ateequr Rehman; Andreas Till; Andrea Rittger; Rainer Podschun; Ulf Meyer-Hoffert; Robert Haesler; Emilie Midtling; Katrin Pütsep; Michael A. McGuckin; Stefan Schreiber; Paul Saftig; Philip Rosenstiel

Objective Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk−/− ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. Design Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk−/− mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. Results Using Ctsk−/− mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk−/− mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk−/− mice ameliorates the severity of intestinal inflammation. Conclusion These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.


The Journal of Neuroscience | 2015

β-Secretase BACE1 Regulates Hippocampal and Reconstituted M-Currents in a β-Subunit-Like Fashion

Sabine Hessler; Fang Zheng; Stephanie Hartmann; Andrea Rittger; Sandra Lehnert; Meike Völkel; Matthias Nissen; Elke Edelmann; Paul Saftig; Michael Schwake; Tobias Huth; Christian Alzheimer

The β-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimers disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1−/− mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1-deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a β-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain.


Obesity | 2013

Genetic and biochemical evidence for a functional role of BACE1 in the regulation of insulin mRNA expression

Albrecht Hoffmeister; Jan Tuennemann; Ines Sommerer; Joachim Mössner; Andrea Rittger; Dorit Schleinitz; Jürgen Kratzsch; Jonas Rosendahl; Nora Klöting; Tobias Stahl; Steffen Roßner; Federico Paroni; Kathrin Maedler; Peter Kovacs; Matthias Blüher

Beta‐site amyloid precursor protein cleaving enzyme (BACE1) is highly expressed in pancreatic β‐cells. The BACE1 gene is located in a region associated with a high diabetes risk in PIMA Indians.


Biochemical and Biophysical Research Communications | 2015

Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

J. Peters; Andrea Rittger; Rebecca Weisner; Johannes Knabbe; Friederike Zunke; Michelle Rothaug; Markus Damme; Samuel F. Berkovic; Judith Blanz; Paul Saftig; Michael Schwake

The lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) has been identified as a receptor for enterovirus 71 uptake and mannose-6-phosphate-independent lysosomal trafficking of the acid hydrolase β-glucocerebrosidase. Here we show that LIMP-2 undergoes proteolytic cleavage mediated by lysosomal cysteine proteases. Heterologous expression and in vitro studies suggest that cathepsin-F is mainly responsible for the lysosomal processing of wild-type LIMP-2. Furthermore, examination of purified lysosomes revealed that LIMP-2 undergoes proteolysis in vivo. Mutations in the gene encoding cathepsin-F (CTSF) have recently been associated with type-B-Kufs-disease, an adult form of neuronal ceroid-lipofuscinosis. In this study we show that disease-causing cathepsin-F mutants fail to cleave LIMP-2. Our findings provide evidence that LIMP-2 represents an in vivo substrate of cathepsin-F with relevance for understanding the pathophysiology of type-B-Kufs-disease.


Journal of Molecular and Cellular Cardiology | 2015

BACE1 modulates gating of KCNQ1 (Kv7.1) and cardiac delayed rectifier KCNQ1/KCNE1 (IKs)

Marianne Agsten; Sabine Hessler; Sandra Lehnert; Tilmann Volk; Andrea Rittger; Stephanie Hartmann; Christian Raab; Doo Yeon Kim; Teja W. Groemer; Michael Schwake; Christian Alzheimer; Tobias Huth

KCNQ1 (Kv7.1) proteins form a homotetrameric channel, which produces a voltage-dependent K(+) current. Co-assembly of KCNQ1 with the auxiliary β-subunit KCNE1 strongly up-regulates this current. In cardiac myocytes, KCNQ1/E1 complexes are thought to give rise to the delayed rectifier current IKs, which contributes to cardiac action potential repolarization. We report here that the type I membrane protein BACE1 (β-site APP-cleaving enzyme 1), which is best known for its detrimental role in Alzheimers disease, but is also, as reported here, present in cardiac myocytes, serves as a novel interaction partner of KCNQ1. Using HEK293T cells as heterologous expression system to study the electrophysiological effects of BACE1 and KCNE1 on KCNQ1 in different combinations, our main findings were the following: (1) BACE1 slowed the inactivation of KCNQ1 current producing an increased initial response to depolarizing voltage steps. (2) Activation kinetics of KCNQ1/E1 currents were significantly slowed in the presence of co-expressed BACE1. (3) BACE1 impaired reconstituted cardiac IKs when cardiac action potentials were used as voltage commands, but interestingly augmented the IKs of ATP-deprived cells, suggesting that the effect of BACE1 depends on the metabolic state of the cell. (4) The electrophysiological effects of BACE1 on KCNQ1 reported here were independent of its enzymatic activity, as they were preserved when the proteolytically inactive variant BACE1 D289N was co-transfected in lieu of BACE1 or when BACE1-expressing cells were treated with the BACE1-inhibiting compound C3. (5) Co-immunoprecipitation and fluorescence recovery after photobleaching (FRAP) supported our hypothesis that BACE1 modifies the biophysical properties of IKs by physically interacting with KCNQ1 in a β-subunit-like fashion. Strongly underscoring the functional significance of this interaction, we detected BACE1 in human iPSC-derived cardiomyocytes and murine cardiac tissue and observed decreased IKs in atrial cardiomyocytes of BACE1-deficient mice.


Science | 2006

Control of peripheral nerve myelination by the beta-secretase BACE1.

Michael Willem; Alistair N. Garratt; Bozidar Novak; Martin Citron; Steve Kaufmann; Andrea Rittger; Bart DeStrooper; Paul Saftig; Carmen Birchmeier; Christian Haass

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Christian Alzheimer

Katholieke Universiteit Leuven

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Sabine Hessler

University of Erlangen-Nuremberg

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Sandra Lehnert

University of Erlangen-Nuremberg

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Stephanie Hartmann

University of Erlangen-Nuremberg

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