TY - JOUR
T1 - Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models
AU - Huang, Yunhong
AU - Skwarek-Maruszewska, Aneta
AU - Horré, Katrien
AU - Vandewyer, Elke
AU - Wolfs, Leen
AU - Snellinx, An
AU - Saito, Takashi
AU - Radaelli, Enrico
AU - Corthout, Nikky
AU - Colombelli, Julien
AU - Lo, Adrian C
AU - Van Aerschot, Leen
AU - Callaerts-Vegh, Zsuzsanna
AU - Trabzuni, Daniah
AU - Bossers, Koen
AU - Verhaagen, Joost
AU - Ryten, Mina
AU - Munck, Sebastian
AU - D'Hooge, Rudi
AU - Swaab, Dick F
AU - Hardy, John
AU - Saido, Takaomi C
AU - De Strooper, Bart
AU - Thathiah, Amantha
N1 - Copyright © 2015, American Association for the Advancement of Science.
PY - 2015/10/14
Y1 - 2015/10/14
N2 - 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.
AB - 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.
U2 - 10.1126/scitranslmed.aab3492
DO - 10.1126/scitranslmed.aab3492
M3 - Article
C2 - 26468326
SN - 1946-6234
VL - 7
SP - 309ra164
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 309
ER -