文献类型：期刊文献

英文题名：Dynamic alteration of neprilysin and endothelin-converting enzyme in age-dependent APPswe/PS1dE9 mouse model of Alzheimer's disease

作者：Zhou, Li[1];Liu, Jianxu[1];Dong, Dong[1];Wei, Chunsheng[1];Wang, Rui[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd, Shanghai 200237, Peoples R China

年份：2017

卷号：9

期号：1

起止页码：184

外文期刊名：AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000393204100016)】；

基金：This project was supported by the grants (to Rui Wang) from National Natural Science Foundation of China 81072627; the 111 Project (Grant No. B07023) from Ministry of Education; Pujiang talent project (11PJ1402300); Key project from Shanghai Science and Technology Committee (12431900901).

语种：英文

外文关键词：A beta; neprilysin; endothelin converting enzyme; colocalization; enzyme activity; Alzheimer's disease

摘要：Imbalance of A beta production and A beta removal leads to A beta accumulation. A beta degrading enzyme (including neprilysin-NEP, endothelin converting enzyme-ECE) as a therapeutic strategy for lowering brain A beta deposition has attracted increasing attention. In this study, we investigated alteration of age and region-dependent in APP/PS1 double transgenic mice (3, 6, 9, 12 months) and their age-matched wild type mice including the ability of spatial memory, A beta deposits, the protein expression, location and activity of NEP and ECE. Our data demonstrated that, as compared with wild type mice, APP/PS1 mice displayed significant cognitive deficit at 9 month revealed by obviously longer in the latency and distance to find the platform and shorter in time spent and swimming distance in the target quadrant. A beta(40) and A beta(42) levels exhibited a significant increase with age in the cerebral cortex and hippocampus of APP/PS1 mice after 6 month, compared with their age-matched wild type mice. And A beta(42) levels were significantly higher than A beta(40) levels in the same age of APP/PS1 mice. Furthermore, NEP protein and activity displayed a marked decrease with age in the cerebral cortex and hippocampus of APP/PS1 mice older than 6 month. Slightly different from NEP, ECE protein was up-regulated with age, while ECE activity showed a significantly decrease with age in cortex and hippocampus of APP/PS1 mice older than 6 month. Double immunofluorescence staining also demonstrated that ECE and NEP highly colocalized in cytoplasmic and membrane, and ECE immunoreactivity tended to increase with age in APP/PS1 mice, especially 12 month APP/PS1 mice. Correlation analysis showed the negative correlation between enzyme (NEP or ECE) activity and A beta levels in the cerebral cortex and hippocampus of APP/PS1 mice, which was correlated with A beta accumulation. These results indicate NEP rather than ECE plays more important role in resisting A beta accumulation. The compensatory upregulation of NEP and ECE could balance A beta metabolism and protect neuronal functions in infant and juvenile mice. These evidence might provide some clues for the treatment of Alzheimer's disease.