BACKGROUND The vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex system, an ubiquitous multiprotein assembly responsible for sorting and trafficking protein cargos out of the endosomes. VPS35 can regulate APP metabolism and Aβ formation, and its levels are reduced in Alzheimer's disease (AD) brains. We and others demonstrated that VPS35 genetic manipulation modulates the phenotype of mouse models of AD. However, the translational value of this observation remains to be investigated. METHODS Triple transgenic mice were randomized to receive a pharmacological chaperone, which stabilizes the retromer complex, and the effect on their AD-like phenotype assessed. RESULTS Compared with controls, treated mice had a significant improvement in learning and memory, an elevation of VPS35 levels, and improved synaptic integrity. Additionally, the same animals had a significant decrease in Aβ levels and deposition, reduced tau phosphorylation and less astrocytes activation. CONCLUSIONS Our study demonstrates that the enhancement of retromer function by pharmacological chaperones is a potentially novel and viable therapy against AD.

中文翻译：

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在具有斑块和缠结的小鼠模型中，药理伴侣可以通过减少Aβ和tau神经病理来改善记忆。

背景技术液泡蛋白分选35（VPS35）是逆转录复合物系统的主要组成部分，其是普遍存在的多蛋白装配体，其负责将蛋白货物分选和运输出内体。VPS35可以调节APP代谢和Aβ的形成，其水平在阿尔茨海默氏病（AD）大脑中降低。我们和其他人证明了VPS35遗传操纵调节AD小鼠模型的表型。但是，这种观察的翻译价值仍有待研究。方法将三只转基因小鼠随机接受药理伴侣，以稳定逆转录复合物，并评估其对AD样表型的影响。结果与对照组相比，经治疗的小鼠的学习和记忆能力显着改善，VPS35水平升高，并改善突触完整性。此外，同一只动物的Aβ水平和沉积显着降低，tau磷酸化程度降低，星形胶质细胞活化降低。结论我们的研究表明，通过药理分子伴侣增强逆转录酶功能是一种潜在的新颖且可行的抗AD疗法。