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Science 323 (5916): 946-951

Copyright © 2009 by the American Association for the Advancement of Science

The Orphan G Protein–Coupled Receptor 3 Modulates Amyloid-Beta Peptide Generation in Neurons

Amantha Thathiah,1,2 Kurt Spittaels,3* Marcel Hoffmann,3{dagger} Mik Staes,3{ddagger} Adrian Cohen,3§ Katrién Horré,1,2 Mieke Vanbrabant,1,2 Frea Coun,4 Veerle Baekelandt,4 André Delacourte,6 David F. Fischer,5|| Dirk Pollet,3 Bart De Strooper,1,2|| Pascal Merchiers3

Abstract: Deposition of the amyloid-β peptide is a pathological hallmark of Alzheimer's disease. A high-throughput functional genomics screen identified G protein–coupled receptor 3 (GPR3), a constitutively active orphan G protein–coupled receptor, as a modulator of amyloid-β production. Overexpression of GPR3 stimulated amyloid-β production, whereas genetic ablation of GPR3 prevented accumulation of the amyloid-β peptide in vitro and in an Alzheimer's disease mouse model. GPR3 expression led to increased formation and cell-surface localization of the mature {gamma}-secretase complex in the absence of an effect on Notch processing. GPR3 is highly expressed in areas of the normal human brain implicated in Alzheimer's disease and is elevated in the sporadic Alzheimer's disease brain. Thus, GPR3 represents a potential therapeutic target for the treatment of Alzheimer's disease.

1 Department of Molecular and Developmental Genetics, Vlaams Institute for Biotechnology.
2 Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium.
3 Galapagos, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
4 Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine, Catholic University of Leuven, Kapucijnenvoer 33, 3000 Leuven.
5 BioFocus DPI, a Galapagos company, Darwinweg 24, 2333 CR Leiden, Netherlands.
6 INSERM Unit 837, Jean-Pierre Aubert Research Center, 1 Place de Verdun, 59045 Lille Cedex, France.

* Present address: Tibotec BVBA, Generaal De Wittelaan L11B3, 2800 Mechelen, Belgium.

{dagger} Present address: Avantium Technologies B.V., Zekeringstraat 29, 1014 BV Amsterdam, Netherlands.

{ddagger} Present address: Terumo Europe NV, Interleuvenlaan 40, 3001 Leuven, Belgium.

§ Present address: Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, 6500HB Nijmegen, Netherlands.

Present address: Ablynx NV, Technologie Park 4, 9052 Zwijnaarde, Belgium.

|| To whom correspondence should be addressed. E-mail: david.fischer{at} (D.F.F.); bart.destrooper{at} (B.D.S.)

International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands.
A. P. Davenport, S. P. H. Alexander, J. L. Sharman, A. J. Pawson, H. E. Benson, A. E. Monaghan, W. C. Liew, C. P. Mpamhanga, T. I. Bonner, R. R. Neubig, et al. (2013)
Pharmacol. Rev. 65, 967-986
   Abstract »    Full Text »    PDF »
Loss of PAFAH1B2 Reduces Amyloid-{beta} Generation by Promoting the Degradation of Amyloid Precursor Protein C-Terminal Fragments.
R. M. Page, A. Munch, T. Horn, P.-H. Kuhn, A. Colombo, O. Reiner, M. Boutros, H. Steiner, S. F. Lichtenthaler, and C. Haass (2012)
J. Neurosci. 32, 18204-18214
   Abstract »    Full Text »    PDF »
The Purinergic Receptor P2X7 Triggers {alpha}-Secretase-dependent Processing of the Amyloid Precursor Protein.
C. Delarasse, R. Auger, P. Gonnord, B. Fontaine, and J. M. Kanellopoulos (2011)
J. Biol. Chem. 286, 2596-2606
   Abstract »    Full Text »    PDF »
Proteases and Proteolysis in Alzheimer Disease: A Multifactorial View on the Disease Process.
B. De Strooper (2010)
Physiol Rev 90, 465-494
   Abstract »    Full Text »    PDF »
G Protein-Coupled Receptors, Cholinergic Dysfunction, and A{beta} Toxicity in Alzheimer's Disease.
A. Thathiah and B. De Strooper (2009)
Science Signaling 2, re8
   Abstract »    Full Text »    PDF »

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