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.
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, 351-0198 Saitama, Japan. Japan Science and Technology Agency, 332-0012 Saitama, Japan.
Sci Transl Med. 2015 Oct 14;7(309):309ra164. doi: 10.1126/scitranslmed.aab3492.
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.
孤儿 G 蛋白（三聚体鸟苷酸结合蛋白）-偶联受体（GPCR）GPR3 在不影响 Notch 蛋白水解的情况下调节 γ-分泌酶复合物的活性，为阿尔茨海默病（AD）提供了一个潜在的治疗靶点。然而，鉴于开发和评估任何新的 AD 治疗方法所需的大量资源，以及转化研究中涉及的多次失败，在启动昂贵的药物开发计划之前，有必要在多个与疾病相关的模型中证明研究结果的病理生理学相关性。我们评估了 Gpr3 在四种 AD 转基因小鼠模型中的生理后果，包括两种含有人源化鼠 Aβ 序列并表达与野生型小鼠相似的 APP 水平的模型，从而减少了潜在的人工表型。我们的研究结果表明，Gpr3 的基因缺失减少了所有 AD 小鼠模型中的淀粉样蛋白病理，并缓解了 APP/PS1 小鼠的认知缺陷。对淀粉样斑块负担的额外三维可视化和分析提供了关于结构完整成年小鼠大脑中淀粉样蛋白负荷、分布和体积的准确信息。对 10 个不同的健康人类尸检脑组织区域进行分析表明，GPR3 表达在衰老过程中是稳定的。然而，两批人类 AD 尸检脑组织样本显示，GPR3 表达升高与 AD 进展之间存在相关性。总的来说，这些研究提供了证据表明，GPR3 在四种 AD 转基因小鼠模型中介导 APP 的淀粉样蛋白水解以及野生型小鼠中 APP 的生理处理，表明 GPR3 可能是 AD 药物开发的潜在治疗靶点。
