[en] The beta-amyloid peptide (Abeta) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the beta-amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase. BACE1 cleaves APP at the N terminus of the Abeta domain, generating a membrane-bound C-terminal fragment (CTF-beta) that can be subsequently cleaved by gamma-secretase within the transmembrane domain to release Abeta. Because BACE1 initiates Abeta generation, it represents a potential target molecule to interfere with Abeta production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, gamma-ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF-beta generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of Abeta. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and Abeta generation. Thus, GGA proteins might be involved in the pathogenesis of AD.
Disciplines :
Neurologie
Auteur, co-auteur :
Wahle, Tina; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Thal, Dietmar R; Institute of Neuropathology, University of Bonn, 53127 Bonn, Germany
Sastre, Magdalena; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Rentmeister, Andrea; Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn, 53127 Bonn, Germany
Bogdanovic, Nenad; Karolinska Institute, Neurotec, Geriatric Department, Huddinge Brain Bank Klinisk Forskingscentrum, 14186 Stockholm, Sweden
Famulok, Michael; Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn, 53127 Bonn, Germany
HENEKA, Michael ; Department of Neurology, University of Bonn, 53127 Bonn, Germany ; Department of Neurology, University of Munster, 48149 Munster, Germany
Walter, Jochen; Department of Neurology, University of Bonn, 53127 Bonn, Germany ; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
GGA1 is expressed in the human brain and affects the generation of amyloid beta-peptide.
Aguzzi A, Haass C (2003) Games played by rogue proteins in prion disorders and Alzheimer's disease. Science 302:814-818.
Andersen OM, Schmidt V, Spoelgen R, Gliemann J, Behlke J, Galatis D, McKinstry WJ, Parker MW, Masters CL, Hyman BT, Cappai R, Willnow TE (2006) Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry 45:2618-2628.
Annaert W, de Strooper B (2002) A cell biological perspective on Alzheimer's disease. Annu Rev Cell Dev Biol 18:25-51.
Boman AL, Zhang C, Zhu X, Kahn RA (2000) A family of ADP-ribosylation factor effectors that can alter membrane transport through the trans-Golgi. Mol Biol Cell 11:1241-1255.
Bonifacino JS (2004) The GGA proteins: adaptors on the move. Nat Rev Mol Cell Biol 5:23-32.
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239-259.
Capell A, Steiner H, Willem M, Kaiser H, Meyer C, Walter J, Lammich S, Multhaup G, Haass C (2000) Maturation and pro-peptide cleavage of beta-secretase. J Biol Chem 275:30849-30854.
Creemers JW, Dominguez DI, Plets E, Serneels L, Taylor NA, Multhaup G, Craessaerts K, Annaert W, de Strooper B (2000) Processing of beta-secretase (Bace) by furin and other members of the proprotein convertase family. J Biol Chem 8:8.
Dell'Angelica EC, Puertollano R, Mullins C, Aguilar RC, Vargas JD, Hartnell LM, Bonifacino JS (2000) GGAs: a family of ADP ribosylation factor-binding proteins related to adaptors and associated with the Golgi complex. J Cell Biol 149:81-94.
Diaz E, Pfeffer SR (1998) TIP47: a cargo selection device for mannose 6-phosphate receptor trafficking. Cell 93:433-443.
Doray B, Ghosh P, Griffith J, Geuze HJ, Kornfeld S (2002) Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network. Science 297:1700-1703.
Fluhrer R, Capell A, Westmeyer G, Willem M, Hartung B, Condron MM, Teplow DB, Haass C, Walter J (2002) A non-amyloidogenic function of BACE-2 in the secretory pathway. J Neurochem 81:1011-1020.
Fluhrer R, Multhaup G, Schlicksupp A, Okochi M, Takeda M, Lammich S, Willem M, Westmeyer G, Bode W, Walter J, Haass C (2003) Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation. J Biol Chem 278:5531-5538.
Ghosh P, Kornfeld S (2003) Phosphorylation-induced conformational changes regulate GGAs 1 and 3 function at the trans-Golgi network. J Biol Chem 278:14543-14549.
Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322-325.
Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, Lannfelt L, Selkoe DJ (1995) The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway. Nat Med 1:1291-1296.
Haniu M, Denis P, Young Y, Mendiaz EA, Fuller J, Hui JO, Bennett BD, Kahn S, Ross S, Burgess T, Katta V, Rogers G, Vassar R, Citron M (2000) Characterization of Alzheimer's beta-secretase protein BACE. A pepsin family member with unusual properties. J Biol Chem 275:21099-21106.
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353-356.
He X, Chang WP, Koelsch G, Tang J (2002) Memapsin 2 (beta-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2. FEBS Lett 524:183-187.
He X, Zhu G, Koelsch G, Rodgers KK, Zhang XC, Tang J (2003) Biochemical and structural characterization of the interaction of memapsin 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins. Biochemistry 42:12174-12180.
He X, Li F, Chang WP, Tang J (2005) GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem 280:11696-11703.
Hirst J, Lui WW, Bright NA, Totty N, Seaman MN, Robinson MS (2000) A family of proteins with gamma-adaptin and VHS domains that facilitate trafficking between the trans-Golgi network and the vacuole/lysosome. J Cell Biol 149:67-80.
Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G (2002) Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann Neurol 51:783-786.
Huse JT, Pijak DS, Leslie GJ, Lee VM, Doms RW (2000) Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase. J Biol Chem 275:33729-33737.
Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G (1999) Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 14:419-427.
Jacobsen L, Madsen P, Nielsen MS, Geraerts WP, Gliemann J, Smit AB, Petersen CM (2002) The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines minimum requirements for GGA binding. FEBS Lett 511:155-158.
Koo EH, Squazzo SL (1994) Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem 269:17386-17389.
Lee EB, Zhang B, Liu K, Greenbaum EA, Doms RW, Trojanowski JQ, Lee VM (2005) BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J Cell Biol 168:291-302.
Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA 97:1456 -1460.
Liu K, Doms RW, Lee VM (2002) Glu11 site cleavage and N-terminally truncated abeta production upon BACE overexpression. Biochemistry 41:3128-3136.
Mathews PM, Guerra CB, Jiang Y, Grbovic OM, Kao BH, Schmidt SD, Dinakar R, Mercken M, Hille-Rehfeld A, Rohrer J, Mehta P, Cataldo AM, Nixon RA (2002) Alzheimer's disease-related overexpression of the cation-dependent mannose 6-phosphate receptor increases Abeta secretion: role for altered lysosomal hydrolase distribution in betaamyloidogenesis. J Biol Chem 277:5299-5307.
Meyer C, Zizioli D, Lausmann S, Eskelinen EL, Hamann J, Saftig P, Von Figura K, Schu P (2000) mu1A-adaptin-deficient mice: lethality, loss of AP-1 binding and rerouting of mannose 6-phosphate receptors. EMBO J 19:2193-2203.
Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ (2006) The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci 26:1596-1603.
Pastorino L, Ikin AF, Nairn AC, Pursnani A, Buxbaum JD (2002) The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total A(beta). Mol Cell Neurosci 19:175-185.
Puertollano R, Aguilar RC, Gorshkova I, Crouch RJ, Bonifacino JS (2001) Sorting of mannose 6-phosphate receptors mediated by the GGAs. Science 292:1712-1716.
Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J, Klockgether T, Van Leuven F, Heneka MT (2006) Nonsteroidal antiinflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci USA 103:443-448.
Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 81:741-766.
Shiba T, Kametaka S, Kawasaki M, Shibata M, Waguri S, Uchiyama Y, Wakatsuki S (2004) Insights into the phosphoregulation of beta-secretase sorting signal by the VHS domain of GGA1. Traffic 5:437-448.
Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, John V, et al (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537-540.
Spoelgen R, von Arnim CA, Thomas AV, Peltan ID, Koker M, Deng A, Irizarry MC, Andersen OM, Willnow TE, Hyman BT (2006) Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J Neurosci 26:418-428.
Tamboli IY, Prager K, Barth E, Heneka M, Sandhoff K, Walter J (2005) Inhibition of glycosphingolipid biosynthesis reduces secretion of the beta-amyloid precursor protein and amyloid beta-peptide. J Biol Chem 280:28110-28117.
Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791-1800.
Thal DR, Ghebremedhin E, Orantes M, Wiestler OD (2003) Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287-1301.
The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging 18:S1-S2.
Thinakaran G, Teplow DB, Siman R, Greenberg B, Sisodia SS (1996) Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the "beta-secretase" site occurs in the Golgi apparatus. J Biol Chem 271:9390-9397.
Vassar R, Citron M (2000) Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron 27:419-422.
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, et al. (1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735-741.
von Arnim CA, Tangredi MM, Peltan ID, Lee BM, Irizarry MC, Kinoshita A, Hyman BT (2004) Demonstration of BACE ({beta}-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy. J Cell Sci 117:5437-5445.
Wahle T, Prager K, Raffler N, Haass C, Famulok M, Walter J (2005) GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network. Mol Cell Neurosci 29:453-461.
Walter J, Kaether C, Steiner H, Haass C (2001a) The cell biology of Alzheimer's disease: uncovering the secrets of secretases. Curr Opin Neurobiol 11:585-690.
Walter J, Fluhrer R, Hartung B, Willem M, Kaether C, Capell A, Lammich S, Multhaup G, Haass C (2001b) Phosphorylation regulates intracellular trafficking of beta-secretase. J Biol Chem 276:14634-14641.
Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, Beach T, Sue L, Wong P, Price D, Li R, Shen Y (2003) Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9:3-4.
Zhu Y, Doray B, Poussu A, Lehto VP, Kornfeld S (2001) Binding of GGA2 to the lysosomal enzyme sorting motif of the mannose 6-phosphate receptor. Science 292:1716-1718.
