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

ABSTRACT: The cause of elevated level of amyloid ?-peptide (A?42) 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 ?-secretase activity and A?42 production in neurons. The ?-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 ?-secretase activity and A? plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the ?-secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of ?-secretase activity and A?42 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 A?42 production in AD and identify HNE as a novel therapeutic target upstream of the ?-secretase cleavage of APP.

SUBMITTER: Gwon AR 

PROVIDER: S-EPMC4217088 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature