{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:01:17Z","timestamp":1793037677887,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,4,9]],"date-time":"2012-04-09T00:00:00Z","timestamp":1333929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>The cause of elevated level of amyloid \u03b2\u2010peptide (A\u03b242) in common late\u2010onset sporadic [Alzheimer\u2019s disease (AD)] has not been established. Here, we show that the membrane lipid peroxidation product 4\u2010hydroxynonenal (HNE) is associated with amyloid and neurodegenerative pathologies in AD and that it enhances \u03b3\u2010secretase activity and A\u03b242 production in neurons. The \u03b3\u2010secretase substrate receptor, nicastrin, was found to be modified by HNE in cultured neurons and in brain specimens from patients with AD, in which HNE\u2013nicastrin levels were found to be correlated with increased \u03b3\u2010secretase activity and A\u03b2 plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the \u03b3\u2010secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of \u03b3\u2010secretase activity and A\u03b242 production by HNE were blocked by an HNE\u2010scavenging histidine analog in a 3xTgAD mouse model of AD. These findings suggest a specific molecular mechanism by which oxidative stress increases A\u03b242 production in AD and identify HNE as a novel therapeutic target upstream of the \u03b3\u2010secretase cleavage of APP.<\/jats:p>","DOI":"10.1111\/j.1474-9726.2012.00817.x","type":"journal-article","created":{"date-parts":[[2012,3,10]],"date-time":"2012-03-10T18:26:30Z","timestamp":1331403990000},"page":"559-568","source":"Crossref","is-referenced-by-count":95,"title":["Oxidative lipid modification of nicastrin enhances amyloidogenic \u03b3\u2010secretase activity in Alzheimer\u2019s disease"],"prefix":"10.1111","volume":"11","author":[{"given":"A\u2010Ryeong","family":"Gwon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong\u2010Sung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiruma 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