title: Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models.
abstract: The orphan G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR3 regulates activity of the γ-secretase complex in the absence of an effect on Notch proteolysis, providing a potential therapeutic target for Alzheimer's disease (AD). However, given the vast resources required to develop and evaluate any new therapy for AD and the multiple failures involved in translational research, demonstration of the pathophysiological relevance of research findings in multiple disease-relevant models is necessary before initiating costly drug development programs. We evaluated the physiological consequences of loss of Gpr3 in four AD transgenic mouse models, including two that contain the humanized murine Aβ sequence and express similar amyloid precursor protein (APP) levels as wild-type mice, thereby reducing potential artificial phenotypes. Our findings reveal that genetic deletion of Gpr3 reduced amyloid pathology in all of the AD mouse models and alleviated cognitive deficits in APP/PS1 mice. Additional three-dimensional visualization and analysis of the amyloid plaque burden provided accurate information on the amyloid load, distribution, and volume in the structurally intact adult mouse brain. Analysis of 10 different regions in healthy human postmortem brain tissue indicated that GPR3 expression was stable during aging. However, two cohorts of human AD postmortem brain tissue samples showed a correlation between elevated GPR3 and AD progression. Collectively, these studies provide evidence that GPR3 mediates the amyloidogenic proteolysis of APP in four AD transgenic mouse models as well as the physiological processing of APP in wild-type mice, suggesting that GPR3 may be a potential therapeutic target for AD drug development.
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: Aneta
authors.initials: A
authors.lastname: Skwarek-Maruszewska
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Horré
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: Elke
authors.initials: E
authors.lastname: Vandewyer
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Wolfs
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Snellinx
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, 351-0198 Saitama, Japan. Japan Science and Technology Agency, 332-0012 Saitama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: Nikky
authors.initials: N
authors.lastname: Corthout
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
authors.forename: Julien
authors.initials: J
authors.lastname: Colombelli
authors.affiliation: Department of Psychology, Laboratory of Biological Psychology, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Lo
authors.affiliation: Department of Psychology, Laboratory of Biological Psychology, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Van Aerschot
authors.affiliation: Department of Psychology, Laboratory of Biological Psychology, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Callaerts-Vegh
authors.affiliation: Departments of Molecular Neuroscience and Clinical Neuroscience, Reta Lila Weston Research Laboratories, Institute of Neurology, University College London, WC1N 3BG London, UK. Department of Genetics, King Faisal Specialist Hospital and Research Centre, 11211 Riyadh, Saudi Arabia.
authors.forename: Daniah
authors.initials: D
authors.lastname: Trabzuni
authors.affiliation: Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, Netherlands.
authors.forename: Koen
authors.initials: K
authors.lastname: Bossers
authors.affiliation: Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Verhaagen
authors.affiliation: Departments of Molecular Neuroscience and Clinical Neuroscience, Reta Lila Weston Research Laboratories, Institute of Neurology, University College London, WC1N 3BG London, UK.
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Munck
authors.affiliation: Department of Psychology, Laboratory of Biological Psychology, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, Netherlands.
authors.forename: Dick F
authors.initials: DF
authors.lastname: Swaab
authors.affiliation: Departments of Molecular Neuroscience and Clinical Neuroscience, Reta Lila Weston Research Laboratories, Institute of Neurology, University College London, WC1N 3BG London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, 351-0198 Saitama, Japan.
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium. amantha.thathiah@cme.vib-kuleuven.be bart.destrooper@cme.vib-kuleuven.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium. KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, 3000 Leuven, Belgium. amantha.thathiah@cme.vib-kuleuven.be bart.destrooper@cme.vib-kuleuven.be.
authors.forename: Amantha
authors.initials: A
authors.lastname: Thathiah
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology* / Q000628:therapy*; D000818:Animals; D001921:Brain / Q000502:physiology; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D058225:Plaque, Amyloid / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000502:physiology*
chemical_list: C092794:GPR3 protein, human; D043562:Receptors, G-Protein-Coupled