The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons.
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.
Thathiah
Amantha
A
Department of Molecular and Developmental Genetics, Vlaams Institute for Biotechnology, Center for Human Genetics, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium.
Spittaels
Kurt
K
Hoffmann
Marcel
M
Staes
Mik
M
Cohen
Adrian
A
Horré
Katrién
K
Vanbrabant
Mieke
M
Coun
Frea
F
Baekelandt
Veerle
V
Delacourte
André
A
Fischer
David F
DF
Pollet
Dirk
D
De Strooper
Bart
B
Merchiers
Pascal
P
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
D016229:Amyloid beta-Peptides; C092794:GPR3 protein, human; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases