title: The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons.
abstract: Deposition of the amyloid-beta 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-beta production. Overexpression of GPR3 stimulated amyloid-beta production, whereas genetic ablation of GPR3 prevented accumulation of the amyloid-beta 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.
authors.affiliation: Department of Molecular and Developmental Genetics, Vlaams Institute for Biotechnology, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Amantha
authors.initials: A
authors.lastname: Thathiah
authors.forename: Kurt
authors.initials: K
authors.lastname: Spittaels
authors.forename: Marcel
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Mik
authors.initials: M
authors.lastname: Staes
authors.forename: Adrian
authors.initials: A
authors.lastname: Cohen
authors.forename: Katrién
authors.initials: K
authors.lastname: Horré
authors.forename: Mieke
authors.initials: M
authors.lastname: Vanbrabant
authors.forename: Frea
authors.initials: F
authors.lastname: Coun
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: André
authors.initials: A
authors.lastname: Delacourte
authors.forename: David F
authors.initials: DF
authors.lastname: Fischer
authors.forename: Dirk
authors.initials: D
authors.lastname: Pollet
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Pascal
authors.initials: P
authors.lastname: Merchiers
mesh_terms: D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; C092794:GPR3 protein, human; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases