RGD Reference Report - Oxidative lipid modification of nicastrin enhances amyloidogenic ¿-secretase activity in Alzheimer's disease. - Rat Genome Database

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Oxidative lipid modification of nicastrin enhances amyloidogenic ¿-secretase activity in Alzheimer's disease.

Authors: Gwon, A-Ryeong  Park, Jong-Sung  Arumugam, Thiruma V  Kwon, Yong-Kook  Chan, Sic L  Kim, Seol-Hee  Baik, Sang-Ha  Yang, Sunghee  Yun, Young-Kwang  Choi, Yuri  Kim, Saerom  Tang, Sung-Chun  Hyun, Dong-Hoon  Cheng, Aiwu  Dann, Charles E  Bernier, Michel  Lee, Jaewon  Markesbery, William R  Mattson, Mark P  Jo, Dong-Gyu 
Citation: Gwon AR, etal., Aging Cell. 2012 Aug;11(4):559-68. doi: 10.1111/j.1474-9726.2012.00817.x. Epub 2012 Apr 9.
RGD ID: 13801051
Pubmed: PMID:22404891   (View Abstract at PubMed)
PMCID: PMC4217088   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1474-9726.2012.00817.x   (Journal Full-text)

The cause of elevated level of amyloid ß-peptide (Aß42) 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 Aß42 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 Aß 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 Aß42 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 Aß42 production in AD and identify HNE as a novel therapeutic target upstream of the γ-secretase cleavage of APP.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  IDA 13801051protein:increased modification:brainRGD 
Alzheimer's disease  ISONCSTN (Homo sapiens)13801051; 13801051protein:increased modification:brainRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ncstn  (nicastrin)

Genes (Mus musculus)
Ncstn  (nicastrin)

Genes (Homo sapiens)
NCSTN  (nicastrin)


Additional Information