Wang Xin, Huang Timothy, Zhao Yingjun, Zheng Qiuyang, Thompson Robert C, Bu Guojun, Zhang Yun-wu, Hong Wanjin, Xu Huaxi
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361005, China; Degenerative Disease Research Program, Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Degenerative Disease Research Program, Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cell Rep. 2014 Nov 6;9(3):1023-33. doi: 10.1016/j.celrep.2014.09.037. Epub 2014 Oct 23.
Patients with Down syndrome (DS) invariably develop Alzheimer's disease (AD) pathology in their 40s. We have recently found that overexpression of a chromosome 21-encoded microRNA-155 results in decreased levels of the membrane trafficking component, SNX27, diminishing glutamate receptor recycling and thereby impairing synaptic functions in DS. Here, we report a function of SNX27 in regulating β-amyloid (Aβ) generation by modulating γ-secretase activity. Downregulation of SNX27 using RNAi increased Aβ production, whereas overexpression of full-length SNX27, but not SNX27ΔPDZ, reversed the RNAi-mediated Aβ elevation. Moreover, genetic deletion of Snx27 promoted Aβ production and neuronal loss, whereas overexpression of SNX27 using an adeno-associated viral (AAV) vector reduced hippocampal Aβ levels in a transgenic AD mouse model. SNX27 associates with the γ-secretase complex subunit presenilin 1; this interaction dissociates the γ-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Aβ-dependent pathogenesis in both DS and AD.
唐氏综合征（DS）患者在40多岁时总会出现阿尔茨海默病（AD）病理特征。我们最近发现，21号染色体编码的微小RNA-155的过表达会导致膜转运成分SNX27水平降低，减少谷氨酸受体的再循环，从而损害DS患者的突触功能。在此，我们报告SNX27通过调节γ-分泌酶活性来调控β-淀粉样蛋白（Aβ）生成的功能。使用RNA干扰（RNAi）下调SNX27会增加Aβ的产生，而全长SNX27的过表达（而非SNX27ΔPDZ）可逆转RNAi介导的Aβ升高。此外，Snx27的基因缺失会促进Aβ产生和神经元丢失，而在转基因AD小鼠模型中，使用腺相关病毒（AAV）载体过表达SNX27可降低海马体中的Aβ水平。SNX27与γ-分泌酶复合物亚基早老素1相互作用；这种相互作用会使γ-分泌酶复合物解离，从而降低其蛋白水解活性。我们的研究确立了DS和AD中Aβ依赖性发病机制的分子机制。
