Abbreviated Journal Title
Alzheimer's disease; amyloid; lipid peroxidation; nicastrin; oxidative; stress; -secretase; MILD COGNITIVE IMPAIRMENT; GAMMA-SECRETASE; A-BETA; ISCHEMIC-STROKE; NEURONAL DEATH; MOUSE MODEL; STRESS; PEROXIDATION; BRAIN; METABOLISM; Cell Biology; Geriatrics & Gerontology
The cause of elevated level of amyloid beta-peptide (A beta 42) in common late-onset sporadic [Alzheimers 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 beta 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 HNEnicastrin levels were found to be correlated with increased ?-secretase activity and A beta 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 beta 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 beta 42 production in AD and identify HNE as a novel therapeutic target upstream of the ?-secretase cleavage of APP.
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. III; Bernier, Michel; Lee, Jaewon; Markesbery, William R.; Mattson, Mark P.; and Jo, Dong-Gyu, "Oxidative lipid modification of nicastrin enhances amyloidogenic ?-secretase activity in Alzheimer's disease" (2012). Faculty Bibliography 2010s. 2695.