A γ‐secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish

EMBO Reports - Tập 3 Số 7 - Trang 688-694 - 2002
Andrea Geling1,2, Harald Steiner3, Michael Willem3, Laure Bally‐Cuif1,2, Christian Haass3
1GSF‐National Research Center for Environment and Health, Institute of Mammalian Genetics Ingolstaedter Landstrasse 1 D‐85764 Neuherberg Germany
2Zebrafish Neurogenetics Junior Research Group, Institute for Virology, Technical University Munich Trogerstrasse 4b D‐81675 Munich Germany
3Adolf Butenandt Institute, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig Maximilians University Munich, Department of Biochemistry Schillerstrasse 44 D-80336 Munich Germany

Tóm tắt

Inhibition of amyloid β‐peptide (Aβ) production by blocking γ‐secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. γ‐secretase inhibitors apparently block Aβ generation via interference with presenilin (PS) function. Besides being an essential component of the γ‐secretase complex, PS itself may be an aspartyl protease with γ‐secretase activity, which is not only required for Aβ production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known γ‐secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels. This indicates severe side‐effects of γ‐secretase inhibitors in any Notch‐dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Aβ production, but not Notch signaling, under in vivo conditions.

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Tài liệu tham khảo

10.1097/00005072-199808000-00003

10.1046/j.1471-4159.2000.0750583.x

10.1093/hmg/9.6.945

10.1242/dev.124.22.4557

10.1074/jbc.273.6.3205

10.1016/S0959-4388(99)80003-8

10.1038/360672a0

10.1083/jcb.200104045

10.1038/ncb1001-e221

10.1038/19083

10.1073/pnas.161102498

10.1101/gad.13.21.2801

10.1016/S0925-4773(97)00037-3

10.1046/j.1471-4159.2001.00012.x

10.1126/science.1064638

10.1038/35017062

10.1242/dev.125.3.359

10.1073/pnas.131202798

10.1038/35017105

10.1016/0169-328X(94)00257-F

10.1101/gad.14.13.1678

10.1002/cne.1059

10.1242/dev.123.1.205

10.1038/35044091

10.1002/aja.1002030302

10.1021/bi991453n

10.1006/scdb.1998.0266

10.1073/pnas.110126897

10.1038/35015085

10.1385/JMN:15:3:189

10.1006/dbio.2000.9960

10.1038/nn0901-887

10.1038/35074581

10.1016/S0955-0674(00)00163-0

Reifers F., 1998, Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain–hindbrain boundary development and somitogenesis, Development, 125, 2381, 10.1242/dev.125.13.2381

10.1093/embo-reports/kve180

10.1038/30756

10.1038/35043065

10.1074/jbc.274.40.28669

10.1038/35041097

10.1242/dev.126.9.1811

10.1074/jbc.272.45.28415

10.1242/dev.119.4.1203

van Eeden F.J., 1996, Mutations affecting somite formation and patterning in the zebrafish, Danio rerio, Development, 123, 153, 10.1242/dev.123.1.153

10.1016/S0896-6273(00)00051-9

10.1074/jbc.272.35.22364

10.1242/dev.122.1.271

10.1242/dev.116.4.931

10.1002/elps.1150180332

10.1021/bi991080q

10.1021/bi982562p

10.1038/19077

10.1073/pnas.191284198

10.1242/dev.125.17.3389

10.1016/S0896-6273(01)00417-2

10.1038/35017108

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EMBO Reports

Tập 3 Số 7

688-694

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