Knock-down of protein L-isoaspartyl O-methyltrans- ferase increases β-amyloid production by decreasing ADAMIO and ADAM17 levels  

作　　者：Narkhyun BAE Se Eun BYEON Jihyuk SONG Sang-Jin LEE Moosik KWON Inhee MOOK-JUNG Jae Youl CHO Sungyoul HONG 

机构地区：[1]Department of Genetic Engineering, Sungkyunkwan University, Suwon 440- 746, Republic of Korea [2]Department of Biochemistry and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110- 799, Republic of Korea

出　　处：《Acta Pharmacologica Sinica》2011年第3期288-294,共7页中国药理学报（英文版）

摘　　要：Aim： To examine the role of protein L-isoaspartyl O-methyltransferase （PIMT; EC 2.1.1.77） on the secretion of Aβ peptides. Methods： HEK293 APPsw cells were treated with PIMT siRNA or adenosine dialdehyde （AdOX）, a broad-spectrum methyltransferase inhibitor. Under the conditions, the level of Aβ secretion and regulatory mechanism by PIMT were examined. Results： Knock-down of PIMT and treatment with AdOX significantly increased Aβ40 secretion. Reductions in levels of PIMT decreased the secretion of soluble amyloid precursor protein alpha （sAPPa） without altering the total expression of APP or its membrane-bound C83 fragment. However, the levels of the C99 fragment generated by β-secretase were enhanced. Moreover, the decreased secretion of sAPPα resulting from PIMT knock-down seemed to be linked with the suppression of the expression of α-secretase gene products, α-disintegrin and metalloprotease 10 （ADAMIO） and ADAM17, as indicated by Western blot analysis. In contrast, ADAMIO was not down-regulated in response to treatment with the protein arginine methyltransferase （PRMT） inhibitor, AMI-1. Conclusion： This study demonstrates a novel role for PIMT, but not PRMT, as a negative regulator of Aβ peptide formation and a potential protective factor in the pathogenesis of AD.Aim： To examine the role of protein L-isoaspartyl O-methyltransferase （PIMT; EC 2.1.1.77） on the secretion of Aβ peptides. Methods： HEK293 APPsw cells were treated with PIMT siRNA or adenosine dialdehyde （AdOX）, a broad-spectrum methyltransferase inhibitor. Under the conditions, the level of Aβ secretion and regulatory mechanism by PIMT were examined. Results： Knock-down of PIMT and treatment with AdOX significantly increased Aβ40 secretion. Reductions in levels of PIMT decreased the secretion of soluble amyloid precursor protein alpha （sAPPa） without altering the total expression of APP or its membrane-bound C83 fragment. However, the levels of the C99 fragment generated by β-secretase were enhanced. Moreover, the decreased secretion of sAPPα resulting from PIMT knock-down seemed to be linked with the suppression of the expression of α-secretase gene products, α-disintegrin and metalloprotease 10 （ADAMIO） and ADAM17, as indicated by Western blot analysis. In contrast, ADAMIO was not down-regulated in response to treatment with the protein arginine methyltransferase （PRMT） inhibitor, AMI-1. Conclusion： This study demonstrates a novel role for PIMT, but not PRMT, as a negative regulator of Aβ peptide formation and a potential protective factor in the pathogenesis of AD.

关 键 词：Alzheimer＇s disease β-amyloid protein L-isoaspartyl O-methyltransferase soluble amyloid precursor protein alpha ADAMIO ADAM 17 

分 类 号：Q523[生物学—生物化学] Q51