Susceptibility of amyloid beta peptide degrading enzymes to oxidative damage: a potential Alzheimer's disease spiral.
Insulysin (IDE) and neprilysin (NEP) were found to be inactivated by oxidation with hydrogen peroxide, an iron-ascorbate oxidation system, and by treatment with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). In each case reaction led to the introduction of protein carbonyl groups as judged by reaction with 2,4-dintrophenylhydrazine. IDE was inactivated by reaction with 4-hydroxy-2-nonenal (HNE) with the concomitant formation of protein adducts. NEP was not inactivated to a significant extent by HNE, but some HNE-adduct formation did occur. Prior reaction with hydrogen peroxide or AAPH led to enhanced formation of HNE adducts. Treatment of IDE with AAHP or hydrogen peroxide increased its susceptibility to proteolysis, while treatment of NEP with iron/ascorbate or hydrogen peroxide increased its susceptibility to proteolysis. Since IDE and NEP play a prominent role in the clearance of amyloid beta peptides, their oxidative inactivation and enhanced proteolysis can contribute to the onset and/or progression of Alzheimer's disease.
Shinall
Heather
H
Department of Molecular and Cellular Biochemistry and the Center for Structural Biology, University of Kentucky, Lexington, Kentucky 40536, USA.
Song
Eun Suk
ES
Hersh
Louis B
LB
D000447:Aldehydes / Q000737:chemistry; D000544:Alzheimer Disease / Q000209:etiology / Q000503:physiopathology*; D000578:Amidines / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001205:Ascorbic Acid / Q000737:chemistry; D002712:Chlorides; D002918:Chymotrypsin / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry; D007339:Insulysin / Q000037:antagonists & inhibitors*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D014357:Trypsin / Q000378:metabolism
D000447:Aldehydes; D000578:Amidines; D016229:Amyloid beta-Peptides; D002712:Chlorides; D005290:Ferric Compounds; C046728:2,2'-azobis(2-amidinopropane); D006861:Hydrogen Peroxide; D002918:Chymotrypsin; D014357:Trypsin; D015260:Neprilysin; D007339:Insulysin; C027576:4-hydroxy-2-nonenal; D001205:Ascorbic Acid; C024555:ferric chloride