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  • Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels.

Knock-down of protein L-isoaspartyl O-methyltransferase increases β-amyloid production by decreasing ADAM10 and ADAM17 levels.

Acta pharmacologica Sinica (2011-03-05)
Narkhyun Bae, Se Eun Byeon, Jihyuk Song, Sang-Jin Lee, Moosik Kwon, Inhee Mook-Jung, Jae Youl Cho, Sungyoul Hong
ABSTRACT

To examine the role of protein L-isoaspartyl O-methyltransferase (PIMT; EC 2.1.1.77) on the secretion of Aβ peptides. 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. Knock-down of PIMT and treatment with AdOX significantly increased Aβ(40) secretion. Reductions in levels of PIMT decreased the secretion of soluble amyloid precursor protein alpha (sAPPα) 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 (ADAM10) and ADAM17, as indicated by Western blot analysis. In contrast, ADAM10 was not down-regulated in response to treatment with the protein arginine methyltransferase (PRMT) inhibitor, AMI-1. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-ADAM 9 Antibody, disintegrin domain, from rabbit
Sigma-Aldrich
Adenosine, periodate oxidized, ≥93%
Sigma-Aldrich
Anti-ADAM 10 Antibody, CT, Chemicon®, from rabbit
Sigma-Aldrich
Anti-ADAM 17 Antibody, Chemicon®, from rabbit