文献类型：期刊文献

英文题名：Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice

作者：Yamasaki R.[1,2];Zhang J.[1,3];Koshiishi I.[4];Sastradipura Suniarti D.F.[1];Wu Z.[1];Peters C.[5];Schwake M.[6];Uchiyama Y.[7];Kira J.-i.[2];Saftig P.[6];Utsumi H.[4];Nakanishi H.[1]

机构：[1]Univ Indonesia, Fac Dent, Dept Oral Biol, Jakarta 10430, Indonesia;[2]Kyushu Univ, Fac Dent Sci, Lab Oral Aging Sci, Fukuoka 812, Japan;[3]Kyushu Univ, Grad Sch Med Sci, Neurol Inst, Dept Neurol, Fukuoka 812, Japan;[4]Shaoxing Univ, Coll Med, Shaoxing, Peoples R China;[5]Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Biofunct Sci, Fukuoka 812, Japan;[6]Univ Freiburg, Inst Mol Med & Zellforschung, D-79106 Freiburg, Germany;[7]Univ Kiel, Dept Biochem, D-24098 Kiel, Germany;[8]Osaka Univ, Grad Sch Med, Dept Cell Biol & Neurosci, Suita, Osaka 565, Japan

年份：2007

卷号：35

期号：4

起止页码：573

外文期刊名：MOLECULAR AND CELLULAR NEUROSCIENCE

收录：SCI-EXPANDED(收录号：WOS:000248796600006)、、Scopus(收录号：2-s2.0-34547417018)、WOS

基金：This study was supported by Grants-in-Aid for Scientific Research (Nos. 17390495 and 17659578 to HN) and a Grant-in-Aid for Scientific Research on Priority Area (No. 15082204 to HN) from the Ministry of Education, Science and Culture, Japan.

语种：英文

外文关键词：microglia; NO; iNOS; CAT-2; AS; cathepsin D; p38 MAP kinase

外文摘要：Nitric oxide (NO) and peroxynitrite, which are produced by activated microglia, are responsible for accelerated neurodegeneration in cathepsin D-deficient (CD-/-) mice. To elucidate the mechanisms by which microglia are initially activated in CD-/- mice, we analyzed the possible relationship between lysosomal storage and microglial activation. In CD-/- mice, the microglial NO-generating activity that was closely associated with the induction of inducible NO synthase and the cationic amino acid transporter-2 (CAT-2) coincided well with the lysosomal storage of subunit c of mitochondrial F0F1ATPase and the formation of ceroid/lipofuscin. Furthermore, activated microglia, which are often accumulating subunit c and ceroid/lipofuscin, showed proliferation activity and an activation of p38 mitogen -activated protein (MAP) kinase. In the primary cultured microglia, pepstatin A was found to enhance the generation of NO and superoxide anion radicals. In these pepstatin A-treated microglia, both an increased generation of the intracellular reactive oxygen species (ROS) and an activation of p38 MAP kinase were observed. These results suggest that the ceroid/lipofuscin which form in microglia activate the p38 MAP kinase cascade through the increased intracellular generation of ROS in CD-/- mice. The activated p38 MAP kinase cascade then promotes the expression of iNOS and CAT-2, thereby inducing the overproduction of NO. (c) 2007 Elsevier Inc. All rights reserved.