文献类型：期刊文献

英文题名：Distinct subcellular patterns of neprilysin protein and activity in the brains of Alzheimer's disease patients, transgenic mice and cultured human neuronal cells

作者：Zhou, Li[1];Wei, Chunsheng[1];Huang, Wei[4];Bennett, David A.[2];Dickson, Dennis W.[3];Wang, Rui[1,4];Wang, Dengshun[4]

机构：[1]E China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;[2]Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA;[3]Mayo Clin, Coll Med, Dept Pathol Neuropathol & Neurosci, Jacksonville, FL 32224 USA;[4]Univ Wisconsin, Dept Pathol & Lab Med, Sch Med & Publ Hlth, Madison, WI USA

年份：2013

卷号：5

期号：6

起止页码：608

外文期刊名：AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000325391000005)】；

基金：This work was supported by the grants to Rui Wang from National Natural Science Foundation of China (81072627); Pujiang talent project of Shanghai (11PJ1402300); Shanghai Committee of Science and Technology (11DZ2260600); 111 Project (Grant No. B07023) and the grants to Dengshun Wang from National Institutes of Health (NIH) grants AG025722 and AG029972, and an Alzheimer's Association grant IIRG-08-90524. The human samples used in this study are from NIH grants to David Bennett (P30AG10161, R01AG15819).

语种：英文

外文关键词：Alzheimer's disease; amyloid-beta; A beta degrading enzymes; neprilysin; subcellular compartments; A beta clearance

摘要：We investigated the subcellular distribution of NEP protein and activity in brains of human individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD dementia, as well as double transgenic mice and human neuronal cell line treated with A beta and 4-hydroxy-2-nonenal (HNE). Total cortical neuronal-related NEP was significantly increased in MCI compared to NCI brains. NeuN was decreased in both MCI and AD, consistent with neuronal loss occurring in MCI and AD. Negative relationship between NEP protein and NeuN in MCI brains, and positive correlation between NEP and pan-cadherin in NCI and MCI brains, suggesting the increased NEP expression in NCI and MCI might be due to membrane associated NEP in non-neuronal cells. In subcellular extracts, NEP protein decreased in cytoplasmic fractions in MCI and AD, but increased in membrane fractions, with a significant increase in the membrane/cytoplasmic ratio of NEP protein in AD brains. By contrast, NEP activity was decreased in AD. Similar results were observed in AD-mimic transgenic mice. Studies of SH-SY5Y neuroblastoma showed an up-regulation of NEP protein in the cytoplasmic compartment induced by HNE and A beta; however, NEP activity decreased in cytoplasmic fractions. Activity of NEP in membrane fractions increased at 48 hours and then significantly decreased after treatment with HNE and A beta. The cytoplasmic/membrane ratio of NEP protein increased at 24 hours and then decreased in both HNE and A beta treated cells. Both HNE and A beta up-regulate NEP expression, but NEP enzyme activity did not show the same increase, possibly indicating immature cytoplasmic NEP is less active than membrane associated NEP. These observations indicate that modulation of NEP protein levels and its subcellular location influence the net proteolytic activity and this complex association might participate in deficiency of A beta degradation that is associated with amyloid deposition in AD.