Research ArticleAlzheimer’s Disease

Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer’s disease mouse models

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Science Translational Medicine  14 Oct 2015:
Vol. 7, Issue 309, pp. 309ra164
DOI: 10.1126/scitranslmed.aab3492

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GPR3, a therapeutic target for AD?

Alzheimer’s disease (AD) is characterized by the degeneration of brain networks involved in cognitive function. AD mouse models are used to study disease pathogenesis, but no single model fully captures the pathological changes in AD patients. Thus, extensive validation of AD therapeutic targets in multiple animal models is required before advancing to clinical research. In new work, Huang et al. determined that the absence of the G protein–coupled receptor 3 (GPR3), a protein expressed in the brain, alleviated the cognitive deficits and reduced amyloid pathology in four different disease-relevant mouse models of AD. Furthermore, GPR3 was found to be elevated in postmortem brain tissue from a subset of AD patients. This study demonstrates that GPR3 is a potential AD therapeutic target and provides the validation needed for future development of GPR3 modulators.


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.

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