Sonderforschungsbereich 415:
"Specifity and Pathophysiology of Signal Transduction Pathways"

Project B9: »Function of the metalloprotease ADAM-10«

An increasing number of transmembrane proteins have been described to become released as soluble fragments by the activity of certain cell surface proteases (secretases). These soluble ectodomains retain their binding capacity and fulfill crucial functions in signal transduction (paracrine, juxtacrine and autocrine signalling). We could show that a deficiency of the secretase ADAM-10 (a disintegrin and metalloprotease) leads to an early lethality at embryonic day 9.5 and a notch-like phenotype in mice. ADAM10 knockout embryos show multiple defects of the developing CNS, somites, and cardiovascular system. Our data concerning the potential contribution of ADAM 10 in a-secretase processing of the Amyloid precursor protein (APP) were very heterogenous showing that APP a-secretase activity was preserved in the majority of the analysed ADAM10 deficient cell lines.

One main focus of our project is the identification of potential ADAM-10 substrates. For this analysis we generated embryonic fibroblast cell lines from wildtype and knockout embryos. In these cell lines the generation of extra- and intracellular cleavage products of different transmembrane proteins will be analysed in the presence and absence of various stimuli (e.g. PMA, cyclodextrin) and inhibitors (e.g. TIMPs, RNAi). In particular, the analysis of EGF- and TNF-family members will be of interest. In another project we plan to analyse the regulation of the proteolytic activity of ADAM-10. We will replace different domains of ADAM10 with the structural homologous domains of the related protease ADAM-17 (TNFa-converting enzyme; TACE) and analyse the proteolytic activity of these chimera on the basis of ADAM-10 and ADAM17 specific substrates. Additionally, we are generating conditional ADAM-10 knockout mice and mice with multiple ADAM deficiencies. With these mouse models we want to analyse the function of ADAM-10, especially in neuronal cells and hope to get more knowledge about the functional redundancy of the major ADAM-proteases.

Our analyses will be based on our ADAM-10 deficient mouse model and our results concerning the role of ADAM-10 in APP- and Notch-processing. The aim of our project is to gain information about the in vivo function of this metalloprotease by the analysis of ADAM-10 deficient embryos and the generated cell lines. One of the goals is to analyse which substrates can be processed by ADAM-10. In addition, the generation and analysis of mice deficient in several ADAMs will help us to understand the redundancy among the ADAM proteases. Furthermore, we want to address the question which factors are important for the regulation of the proteolytic activity. In this context, we want to analyse the functional significance of particular domains of ADAM-10 in comparison to the structural related ADAM-17. In a long-term project, we are generating conditional ADAM-10 deficient mice to be able to analyse the essential function of this protease also in the adult organism and in different tissues, like the nervous system.

The aims of the functional analysis of ADAM-10 are:

• Identification of potential ADAM-10 substrates
• Understanding the role of the different domains/domain structure for the regulation of ADAM-10 activity
• Generation and analysis of knockout mice deficient for several ADAMs
• Generation and analysis of conditional ADAM-10 knockout mice

Original papers

Chalaris A, Adam N, Sina C, Rosenstiel P, Lehmann J, Schirmacher P, Hartmann D, Cichy J, Gavrilova O, Schreiber S, Jostock T, Matthews V, Häsler R, Becker C, Neurath MF, Reiß K, Saftig P, Scheller J, Rose-John S. (2010) Critical Role of the Disintegrin Metalloprotease ADAM17 for Intestinal Inflammation and Regeneration in Mice.

J Exp Med 207:1617-1624

Chalaris A, Adam N, Sina C, Rosenstiel P, Lehmann-Koch J, Schirmacher P, Hartmann D, Cichy J, Gavrilova O, Schreiber S, Jostock T, Matthews V, Häsler R, Becker C, Neurath MF, Reiss K, Saftig P, Scheller J, Rose-John S. (2010) Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice.

J Exp Med 207:1617-1624

Jorissen E, Prox J, Bernreuther C, Weber S, Schwanbeck R, Serneels L, Snellinx A, Craessaerts K, Thathiah A, Tesseur I, Bartsch U, Weskamp G, Blobel CP, Glatzel M, De Strooper B, Saftig P. (2010) The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex.

J Neurosci 30:4833-44

Bloch L, Sineshchekova O, Reichenbach D, Reiss K, Saftig P, Kuro-o M, Kaether C. (2009) Klotho is a substrate for alpha-, beta- and gamma-secretase.

FEBS Lett 583:3221-4

Janes PW, Wimmer-Kleikamp SH, Frangakis AS, Treble K, Griesshaber B, Sabet O, Grabenbauer M, Ting AY, Saftig P, Bastiaens PI, Lackmann M. (2009) Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10.

PLoS Biol 10:e1000215

Reiss K, Saftig P. (2009) The "a disintegrin and metalloprotease" (ADAM) family of sheddases: physiological and cellular functions.

Semin Cell Dev Biol 2:126-37

Steubesand N, Kiehne K, Brunke G, Pahl R, Reiss K, Herzig KH, Schubert S, Schreiber S, Folsch UR, Rosenstiel P, Arlt A. (2009) The expression of the beta-defensins hBD-2 and hBD-3 is differentially regulated by NF-kappaB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis.

BMC Immunol 10:36

Steubesand N, Kiehne K, Brunke G, Pahl R, Reiss K, Herzig KH, Schubert S, Schreiber S, Folsch UR, Rosenstiel P, Arlt A. (2009) The expression of the beta-defensins hBD-2 and hBD-3 is differentially regulated by NF-kappaB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis.

BMC Immunol 10:36

Tousseyn T, Thathiah A, Jorissen E, Raemaekers T, Konietzko U, Reiss K, Maes E, Snellinx A, Serneels L, Nyabi O, Annaert W, Saftig P, Hartmann D, De Strooper B. (2009) ADAM10, the rate-limiting protease of regulated intramembrane proteolysis of Notch and other proteins, is processed by ADAMS-9, ADAMS-15, and the gamma-secretase.

J Biol Chem 284:11738-47

Maretzky T, Scholz F, Köten B, Proksch E, Saftig P, Reiss K. (2008) ADAM10-mediated E-cadherin release Is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis.

J Invest Dermatol 128:1737-46

Maretzky T, Scholz F, Köten B, Proksch E, Saftig P, Reiss K. (2008) ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis.

J Invest Dermatol. 128:1737-46

Maretzky T, Scholz F, Köten B, Proksch E, Saftig P, Reiss K. (2008) ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis.

J Invest Dermatol 128:1737-46

Martin L, Fluhrer R, Reiss K, Kremmer E, Saftig P, Haass C. (2008) Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b.

J Biol Chem 283:1644-52

Raucci A, Cugusi S, Antonelli A, Barabino SM, Monti L, Bierhaus A, Reiss K, Saftig P, Bianchi ME. (2008) A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10).

FASEB J 10:3716-27

Schulz B, Pruessmeyer J, Maretzky T, Ludwig A, Blobel CP, Saftig P, Reiss K. (2008) ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin.

Circ Res 102:1192-201

Eichenauer DA, Simhadri VL, von Strandmann EP, Ludwig A, Matthews V, Reiners KS, von Tresckow B, Saftig P, Rose-John S, Engert A, Hansen HP. (2007) ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro.

Cancer Res 67:332-8

Eichenauer DA, Simhadri VL, von Strandmann EP, Ludwig A, Matthews V, Reiners KS, von Tresckow B, Saftig P, Rose-John S, Engert A, Hansen HP. (2007) ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro.

Cancer Res 67:332-8

Eichenauer DA, Simhadri VL, von Strandmann EP, Ludwig A, Matthews V, Reiners KS, von Tresckow B, Saftig P, Rose-John S, Engert A, Hansen HP (2007) ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro.

Cancer Res, Jan 1;67:332-8

Horiuchi K, Le Gall S, Schulte M, Yamaguchi T, Reiss K, Murphy G, Toyama Y, Hartmann D, Saftig P, Blobel CP. (2007) Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx.

Mol Biol Cell 1:176-88

Hundhausen C, Schulte A, Schulz B, Andrzejewski MG, Schwarz N, von Hundelshausen P, Winter U, Paliga K, Reiss K, Saftig P, Weber C, Ludwig A. (2007) Regulated shedding of transmembrane chemokines by the disintegrin and metalloproteinase 10 facilitates detachment of adherent leukocytes.

J Immunol 178:8064-72

Hundhausen D, Schulte A, Schulz B, Andrzejewski MG, Schwarz N, von Hundelshausen P, Winter U, Paliga K, Reiss K, Saftig P, Weber C, Ludwig A. (2007) Regulated shedding of transmembrane chemokines by the metalloproteinase disintegrin and metalloproteinase 10 facilitates detachment of adherent leukocytes.

J Immunol, in press

Li N, Wang Y, Forbes K, Vignali KM, Heale BS, Saftig P, Hartmann D, Black RA, Rossi JJ, Blobel CP, Dempsey PJ, Workman CJ, Vignali DA. (2007) Metalloproteases regulate T-cell proliferation and effector function via LAG-3.

EMBO J 26:494-504

Li N, Wang Y, Forbes K, Vignali KM, Heale BS, Saftig P, Hartmann D, Black R, Rossi JJ, Blobel C, Dempsey PJ, Workman CJ, Vignali DAA. (2007) Metalloproteinases regulate T cell proliferation and effector function via LAG3.

EMBO J, 26:494-504

Schulte A, Schulz B, Andrzejewski MG, Hundhausen C, Mletzko S, Achilles J, Reiss K, Paliga K, Weber C, Rose-John S, Ludwig A. (2007) Sequential processing of the transmembrane Chemokines CX3CL1 and CXCL16 by a- an g-secretases.

Biophys Res Commun 358:233-240

Schulte M, Reiss K, Lettau M, Maretzky T, Ludwig A, Hartmann D, de Strooper B, Janssen O, Saftig P. (2007) ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death.

Cell Death Differ 14:1040-9

Schulte M, Reiss K, Lettau M, Maretzky T, Ludwig A, Hartmann D, de Strooper B, Janssen O, Saftig P. (2007) ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death.

Cell Death Differ 14:1040-9

Schulte M, Reiss K, Lettau M, Maretzky T, Ludwig A, Hartmann D, de Strooper B, Janssen O, Saftig P. (2007) ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death.

Cell Death Differ 14:1040-9

Schulte M, Reiss K, Lettau M, Maretzky T, Ludwig A, Hartmann D, de Strooper B, Janssen O, Saftig P. (2007) ADAM regulates FasL cell surface expression and modulates FasL-induced cytotoxisity and activation-induced cell death.

Cell Death & Differentiation, in press

Shacka JJ, Klocke BJ, Young C, Shibata M, Olney JW, Uchiyama Y, Saftig P, Roth KA. (2007) Cathepsin D Deficiency Induces Persistent Neurodegeneration in the Absence of Bax-Dependent Apoptosis.

J Neuroscience, in press

Walls KC, Klocke BJ, Saftig P, Shibata M, Uchiyama Y, Roth K, Shaka JJ. (2007) Altered regulation of phosphatidylinisitol 3-kinase signaling in cathepsin D deficient brain.

Autophagy, in press

Yamasaki R, Zhang J, Koshiishi I, Wu IW, Schwake M, Uchiyama Y, Kira J, Saftig P, Utsumi H, Nakanishi H. (2007) Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice.

Mol Cell Neuroscience, in press

Anders L, Mertins P, Lammich S, Murgia M, Hartmann D, de Strooper B, Saftig P, Haass C, Ullrich A. (2006) Furin, ADAM 10 and gamma-Secretase-Mediated Cleavage of a Receptor Tyrosine Phosphatase and Regulation of beta-Catenin's Transcriptional Activity

Mol Cell Biol, 26:3917-34

Bech-Serra JJ, Santiago-Josefat B, Esselens C, Saftig P, Baselga J, Arribas J, Canals F. (2006) Proteomic identification of desmoglein 2 and activated leukocyte cell adhesion molecule as substrates of ADAM17 and ADAM10 by difference gel electrophoresis.

Mol Cell Biol 26:5086-5095

Reiss K, Ludwig A, Saftig P. (2006) Breaking up the tie: disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion

Pharmacology and Therapeutics, 111:985-1006

Reiss K, Maretzky T, Haas IG, Schulte M, Ludwig A, Frank M, Saftig P. (2006) Regulated ADA10-dependent ectodomain shedding of gamma-protocadherin C3 mudulates cell-cell adhesion

J Biol Chem 281:21735-21744

Röcken C, Fändrich M, Stix B, Tannert A, Hortschansky P, Reinheckel T, Saftig P, Kähne T, Menard R, Ancsin JB, Bühling F. (2006) Cathepsin protease activity modulates amyloid-load in extracerebral amyloidosis

J Pathol, Dec;210:478-87

Schwake M, Athanasiadu D, Beimgraben C, Blanz J, Beck C, Jentsch T, Saftig P, Friedrich T. (2006) Structural determinants of M-type KCNQ channel assembly

J Neuroscience, 26:3757-3766

Steinfeld R, Reinhardt K, Schreiber K, Kraetzner R, Hillebrand M, Saftig P, Gärtner J. (2006) Human cathepsin D deficiency is associated with a progressive neurodegenerative disease.

Am J Hum Genet, 78:988-998

Weskamp G, Ford J, Sturgill J, Martin S, Docherty A, Swendeman S, Broadway N, Hartmann D, Saftig P, Umland S, Fujisawa-Sehara A, Black RA, Ludwig A, Becherer JD, Conrad D, Blobel C. (2006) Identification of ADAM10 as a major sheddase of the low affinity IgE receptor CD23.

Nat Immunol 7:1293-1298

Willem M, Garrat A, Novak B, Citron M, Kaufmann S, Rittger A, de Strooper B, Saftig P, Birchmeyer C, Haass C. (2006) Control of peripheral myelination by the b-secretase BACE-1

Science 314:664-666

del Cerro-Vadillo E, Carrasco-Marin E, Beck C, San Cosme-Campo L, Fernandez-Prieto L, Leyva-Cobian F, Saftig P, Alvarez-Dominguez C. (2006) A novel non-oxidative phagosomal mechanism exerted by cathepsin-D controls Listeria monocytogenes intracellular growth

J Immunology, 176:1321-1325

Budagian V, Bulanova E, Orinska Z, Duitman E, Brandt K, Ludwig A, Hartmann D, Lemke G, Saftig P, Bulfone-Paus S. (2005) Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum.

Mol Cell Biol 25:9324-9339

Dominguez D, Tournoy J, Hartmann D, Cryns K, Serneels S, Camacho I, Marjaux E, Anneart W, Roebroeck A, d'Hooge R, Reiss K, Maechears D, Saftig P, de Strooper B. (2005) Phenotypical and biochemical analysis of BACE1 and BACE2 deficient mice.

J Biol Chem 280:30797-30806

Henningsson F, Yamamoto K, Saftig P, Reinheckel T, Knight S, Pejler G. (2005) A role for cathepsin E in the processing of mast cell carboxydase A.

J Cell Science 118:2035-2042

Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, de Strooper B, Hartmann D, Saftig P. (2005) ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration and beta-catenin translocation.

Proc Natl Acad Sci 102:9182-9187

Maretzky T, Schulte M, Ludwig A, Rose-John S, Blobel C, Hartmann D, Altevogt P, Saftig P, Reiss K. (2005) L1 is sequentially processed by two differently activated metalloproteinases and presenilin/g-secretase regulating neural cell adhesion, cell migration and neurite outgrowth.

Mol Cell Biol 25:9040-9053

Reiss K, Maretzky T, Ludwig A, Tousseyn T, de Strooper B, Hartmann D, Saftig P. (2005) ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling

EMBO J 24:742-752

Schenzer A, Friedrich T, Pusch M, Saftig P, Jentsch TJ, Grötzinger J, Schwake M. (2005) Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine

J Neurosci 25:5051-60

Shimizu T, Hayashi Y, Yamada J, Zhang J, Yamasaki R, Ukai K, Koike M, Mine K, von Figura K, Peters C, Saftig P, Uchiyama Y, Nakanishi H. (2005) Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramical cells in cathepsin D-devicient mice

J Neurochem 94:680-690

Willenborg M, Schmidt CK, Braun P, Landgrebe J, von Figura K, Saftig P, Eskelinen EL. (2005) Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation.

J Lipid Res 46:2559-2569

Wong HK, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, Kurosawa M, de Strooper B, Saftig P, Nukina N. (2005) Beta subunits of voltage-gated sodium channels are novel substrates of BACE1 and gamma-secretase.

J Biol chem 280:23009-23017

Abel S, Hundhausen C, Mentlein R, Schulte A, Berkhout TA, Broadway N, Hartmann D, Dietrich S, Muetze B, Schuster B, Kallen KJ, Saftig P, Rose-John S, Ludwig A. (2004) The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10.

J Immunol 172: 6362-6372

Budagian V, Bulanova E, Orinska Z, Ludwig A, Rose-John S, Saftig P, Borden EC, Bulfone-Paus S. (2004) Natural soluble interleukin-15Ralpha is generated by cleavage that involves the tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17).

J Biol Chem 279: 40368-40375

Egberts F, Heinrich M, Jensen JM, Winoto-Morbach S, Pfeiffer S, Wickel M, Schunck, M, Steude J, Saftig P, Proksch E, Schütze S. (2004) Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation.

J. Cell Sci 117: 2295-2307

Nagano O, Murakami D, Hartmann D, de Strooper B, Saftig P, Iwatsubo T, Nakajima M, Shinohara M, Saya H. (2004) Cell-matrix interaction via CD44 is independently regulated by different Metalloproteinases activated in response to extracellular Ca2+ influx and PKC activation.

J Cell Biol. 2004 Jun 21;165:893-902

Sahin U, Weskamp G, Kelly K, Zhou H ,Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel C. (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR-ligands.

J. Cell Biol. 2004 Mar 1;164:769-79

Zheng Y, Saftig P, Hartmann D, Blobel C. (2004) Evaluation of the contribution of different ADAMs to TNFa shedding and of the function of the TNFa ectodomain in ensuring selective stimulated shedding by the TNFa convertase (TACE/ADAM17).

J. Biol Chem. 279:42898-42906

Lichtenthaler SF, Dominguez DI, Westmeyer GG, Reiss K, Haass C, Saftig P, De Strooper B, Seed B. (2003) The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1.

J Biol Chem. 2003 Dec 5;278:48713-9

Matthews V, Schuster B, Schütze S, Bussmeyer I, Ludwig A, Hundhausen C, Sadowski T, Saftig P, Hartmann D, Kallen KJ, Rose-John S. (2003) Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE).

J. Biol. Chem 278: 38829-38839

Weskamp G, Schlondorff J, Lum L, Becherer D, Kim TW, Saftig P, Hartmann D, Murphy G, Blobel CP. (2003) Evidence for a critical role of the TNFalpha convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR).

J Biol Chem.

Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Lübke T, Illert AL, von Figura K, Saftig P. (2002) Deficiency for the disintegrin / metalloprotease ADAM-10 causes disturbed alpha secretase activity and notch deficiency - like phenotype in mice.

Hum Mol Genet. 11:2615-24

Leissring MA, Murphy MP, Mead TR, Akbari Y, Sugarman MC, Jannatipour M, Anliker B, Muller U, Saftig P, De Strooper B, Wolfe MS, Golde TE, LaFerla FM. (2002) A physiologic signaling role for the gamma-secretase-derived intracellular fragment of APP.

Proc Natl Acad Sci U S A. 99:4697-4702

Nyabi O, Pype S, Mercken M, Herreman A, Saftig P, Craessaerts K, Serneels L, Annaert W, De Strooper B. (2002) No endogenous A beta production in presenilin-deficient fibroblasts.

Nat Cell Biol. 4:164

Cupers P, Bentahir M, Craessaerts K, Orlans I, Vanderstichele H, Saftig P, de Strooper B, Annaert W. (2001) The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein.

J. Cell Biol. 154, 731-740

Hartmann D, Tournoy J, Saftig P, Annaert W, De Strooper B. (2001) Implication of APP secretases in notch signaling.

J Mol Neurosci. 17:171-81

Vincent B, Paitel E, Saftig P, Frobert Y, Hartmann D, de Strooper B, Grassi J, Lopez-Perez E, Checler F. (2001) The disintegrins ADAM-10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein.

J Biol Chem. 276:37743-37746.

Wiltfang J, Esselmann H, Cupers P, Neumann M, Kretzschmar H, Beyermann M, Schleuder D, Jahn H, Rüther E, Kornhuber J, Annaert W, de Strooper B, Saftig P. (2001) Elevation of beta-Amyloid Peptide 2-42 in Sporadic and Familial Alzheimer's Disease and Ist Generation in PS1 Knockout Cells.

J. Biol. Chem. 276, 42645-42657

De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular Domain.

Nature 398, 518-522

Hartmann D, de Strooper B, Saftig P. (1999) Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly.

Current Biol. 9, 719-727

Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, van Leuven F, de Strooper B. (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency.

Proc. Natl. Acad. Sci. USA 96, 11872-11877

de Strooper B*, Saftig P*, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, von Figura K, van Leuven F. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.

*equally contributed

Nature 391, 387-390 *equally contributed