title: Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease.
abstract: The cause of elevated level of amyloid β-peptide (Aβ42) in common late-onset sporadic [Alzheimer's disease (AD)] has not been established. Here, we show that the membrane lipid peroxidation product 4-hydroxynonenal (HNE) is associated with amyloid and neurodegenerative pathologies in AD and that it enhances γ-secretase activity and Aβ42 production in neurons. The γ-secretase substrate receptor, nicastrin, was found to be modified by HNE in cultured neurons and in brain specimens from patients with AD, in which HNE-nicastrin levels were found to be correlated with increased γ-secretase activity and Aβ plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the γ-secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of γ-secretase activity and Aβ42 production by HNE were blocked by an HNE-scavenging histidine analog in a 3xTgAD mouse model of AD. These findings suggest a specific molecular mechanism by which oxidative stress increases Aβ42 production in AD and identify HNE as a novel therapeutic target upstream of the γ-secretase cleavage of APP.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: A-Ryeong
authors.initials: AR
authors.lastname: Gwon
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Yong-Kook
authors.initials: YK
authors.lastname: Kwon
authors.forename: Sic L
authors.initials: SL
authors.lastname: Chan
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Sang-Ha
authors.initials: SH
authors.lastname: Baik
authors.forename: Sunghee
authors.initials: S
authors.lastname: Yang
authors.forename: Young-Kwang
authors.initials: YK
authors.lastname: Yun
authors.forename: Yuri
authors.initials: Y
authors.lastname: Choi
authors.forename: Saerom
authors.initials: S
authors.lastname: Kim
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Hyun
authors.forename: Aiwu
authors.initials: A
authors.lastname: Cheng
authors.forename: Charles E
authors.initials: CE
authors.lastname: Dann
authors.forename: Michel
authors.initials: M
authors.lastname: Bernier
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: William R
authors.initials: WR
authors.lastname: Markesbery
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D000447:Aldehydes; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; D008562:Membrane Glycoproteins; D008563:Membrane Lipids; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; C027576:4-hydroxy-2-nonenal