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Oxidative Lipid Modification of Nicastrin Enhances Amyloidogenic ?-Secretase Activity in Alzheimer's Disease

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Oxidative Lipid Modification of Nicastrin Enhances Amyloidogenic ?-Secretase Activity in Alzheimer's Disease University of Central Florida STARS Faculty Bibliography 2010s Faculty Bibliography 1-1-2012 Oxidative lipid modification of nicastrin enhances amyloidogenic ?-secretase activity in Alzheimer's disease A-Ryeong Gwon Jong-Sung Park Thiruma V. Arumugam Yong-Kook Kwon Sic L. Chan University of Central Florida SeeFind next similar page works for additional at: https:/ authors/stars.libr ary.ucf.edu/facultybib2010 University of Central Florida Libraries http://library.ucf.edu This Article is brought to you for free and open access by the Faculty Bibliography at STARS. It has been accepted for inclusion in Faculty Bibliography 2010s by an authorized administrator of STARS. For more information, please contact [email protected]. Recommended Citation 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. https://stars.library.ucf.edu/facultybib2010/2695 Authors A-Ryeong Gwon, Jong-Sung Park, Thiruma V. Arumugam, Yong-Kook Kwon, Sic L. Chan, Seol-Hee Kim, Sang-Ha Baik, Sunghee Yang, Young-Kwang Yun, Yuri Choi, Saerom Kim, Sung-Chun Tang, Dong-Hoon Hyun, Aiwu Cheng, Charles E. Dann III, Michel Bernier, Jaewon Lee, William R. Markesbery, Mark P. Mattson, and Dong-Gyu Jo This article is available at STARS: https://stars.library.ucf.edu/facultybib2010/2695 Aging Cell (2012) 11, pp559–568 Doi: 10.1111/j.1474-9726.2012.00817.x Oxidative lipid modification of nicastrin enhances amyloidogenic c-secretase activity in Alzheimer’s disease A-Ryeong Gwon,1* Jong-Sung Park,1* Thiruma V. production in AD and identify HNE as a novel therapeutic target Arumugam,2,3* Yong-Kook Kwon,4 Sic L. Chan,2,5 upstream of the c-secretase cleavage of APP. Seol-Hee Kim,1 Sang-Ha Baik,1 Sunghee Yang,1 Key words: Alzheimer’s disease; amyloid; lipid peroxidation; Young-Kwang Yun,1 Yuri Choi,1 Saerom Kim,1 Sung-Chun nicastrin; oxidative stress; c-secretase. Tang,2,6 Dong-Hoon Hyun,2,7 Aiwu Cheng,2 Charles E. Dann III,8 Michel Bernier,9 Jaewon Lee,10 William R. Introduction Markesbery,11† Mark P. Mattson2,12 and Dong-Gyu Jo1 1School of Pharmacy, Sungkyunkwan University, Suwon, Korea Alzheimer’s disease (AD), the most common form of dementia, is charac- 2Laboratory of Neurosciences, National Institute on Aging Intramural terized pathologically by the presence of large numbers of neuritic pla- Research Program, Baltimore, MD, USA ques and neurofibrillary tangles (Markesbery, 1997a). The major protein 3 School of Biomedical Sciences, University of Queensland, Brisbane, Qld, component of these plaques is amyloid b-peptide (Ab), a 40- to 42- Australia amino-acid protein derived from amyloid precursor protein (APP) through 4Department of Pathology, University of Pittsburgh, Pittsburgh, USA sequential proteolytic cleavages by b-secretase (BACE) and c-secretase 5College of Medicine, University of Central Florida, Orlando, FL, USA 6Department of Neurology, National Taiwan University Hospital, Yun-Lin (Hardy & Selkoe, 2002). Molecular genetic analyses have demonstrated Branch, Taiwan that mutations in presenilin-1 (PS1) cause many cases of early-onset 7Division of Life and Pharmaceutical Sciences, Ewha Woman’s University, familial AD, and subsequent studies have established that PS1 is an essen- Seoul, Korea tial enzymatic component of c-secretase. Furthermore, mutations in PS1 8 Department of Chemistry, Indiana University, Bloomington, IN, USA have shown to increase the production of Ab42 and the Ab42 ⁄ Ab40 9Laboratory of Clinical Investigation, National Institute on Aging Intramural ratio, which is believed to cause synaptic dysfunction and neuronal death Research Program, Baltimore, MD, USA 10College of Pharmacy, Pusan National University, Pusan, Korea in AD (Mattson, 2004). Three additional transmembrane proteins have 11Sanders-Brown Research Center on Aging, University of Kentucky, been identified as components of the c-secretase complex – nicastrin, Lexington, KY, USA Pen-2, and Aph-1; it has been reported that the ectodomain of nicastrin 12Department of Neuroscience, Johns Hopkins University School of functions as a c-secretase substrate receptor (Shah et al., 2005). How- Medicine, Baltimore, MD, USA ever, although mutations in APP and presenilins can result in increased Summary Ab42 production and AD, the cause of the high accumulation of Ab42 in the most common late-onset sporadic cases of AD has not been The cause of elevated level of amyloid b-peptide (Ab42) in com- determined. mon late-onset sporadic [Alzheimer’s disease (AD)] has not been Ab pathology has been associated with increased cellular oxidative established. Here, we show that the membrane lipid peroxidation stress as demonstrated by elevated levels of oxidatively modified proteins product 4-hydroxynonenal (HNE) is associated with amyloid and and lipids at sites of Ab deposits in patients with AD, transgenic mouse neurodegenerative pathologies in AD and that it enhances c-sec- models of AD, and cultured neurons exposed to synthetic Ab (McLellan retase activity and Ab42 production in neurons. The c-secretase et al., 2003; Murray et al., 2007; Sultana et al., 2009). Furthermore, it substrate receptor, nicastrin, was found to be modified by HNE in has been reported that lipid peroxidation precedes Ab deposition in a cultured neurons and in brain specimens from patients with AD, mouse model of AD (Pratico et al., 2001), which suggests that oxidative in which HNE–nicastrin levels were found to be correlated with stress plays a role in Ab production and accumulation. In fact, the mem- increased c-secretase activity and Ab plaque burden. Furthermore, brane lipid peroxidation product 4-hydroxynonenal (HNE) has been HNE modification of nicastrin enhanced its binding to the c-secre- shown to accumulate in the brain during normal aging and to be associ- tase substrate, amyloid precursor protein (APP) C99. In addition, ated with AD pathology (Montine et al., 1997; Sayre et al., 1997; Cutler the stimulation of c-secretase activity and Ab42 production by et al., 2004; Williams et al., 2006). The mechanism whereby lipid peroxi- HNE were blocked by an HNE-scavenging histidine analog in a dation damages neurons involves the aldehyde HNE, which is liberated 3xTgAD mouse model of AD. These findings suggest a specific from peroxidized membrane fatty acids. In addition, HNE can covalently molecular mechanism by which oxidative stress increases Ab42 modify proteins and may thereby alter their structures and functions. Fur- thermore, it has been suggested that HNE accumulates in membranes at concentrations of 10 lM–5 mM in response to oxidative insults (Uchida, 2003). HNE is known to modify the functions of several membrane-asso- Correspondence Mark P. Mattson, Laboratory of Neurosciences, National Institute on Aging, Balti- ciated proteins in neurons including ion-motive ATPases, the neuronal more, MD 21224, USA. Tel.: +1 410 558 8462; fax: +1 410 558 8465; e-mail: glucose transporter GLUT3, the astrocyte glutamate transporter GLT-1, [email protected]; GTP-binding proteins, and tau (Uchida, 2003). Moreover, the major Ab- Dong-Gyu Jo, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, degrading protease, neprilysin, is modified by HNE in the AD brain and in Cell Korea. Tel.: +82 31 290 7782; fax: +82 31 292 8800; e-mail: [email protected] neuronal cells (Wang et al., 2009). Brain samples of patients with AD homozygous for the apoE e4 *The authors contributed equally to this work. allele exhibit greater HNE adduct immunoreactivity than those of † Deceased. AD patients with other apoE genotypes, which suggests that the Accepted for publication 27 February 2012 capacities of apoE isoforms to detoxify HNE differ (Montine et al., Aging ª 2012 The Authors 559 Aging Cell ª 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 560 Oxidative modification of c-secretase in Alzheimer’s disease, A.-R. Gwon et al. 1997; Pedersen et al., 2000). However, it has not been determined pretreatment with GSH or GSI blocked these c-secretase-dependent whether or how HNE affects the amyloidogenic process in AD. increases in GFP fluorescence. Because Ab can induce membrane lipid peroxidation and HNE production in neurons (Mark et al., 1997), the abil- ity of GSH to block Ab42-induced c-secretase activity suggests that Ab Results may amplify the amyloidogenic processing of APP via HNE-mediated posi- tive feedback activation of c-secretase. No significant changes in cell via- The membrane lipid peroxidation product HNE increases bility were detected under these experimental conditions (Fig. S1). c-secretase activity and Ab production To explore the mechanistic basis for the enhancement of c-secretase To determine whether membrane-associated oxidative stress can affect activity by HNE, c-secretase complex was immunoprecipitated with anti- c-secretase activity, we treated primary cultured rat cerebral cortical neu- PS1-CTF antibody from SH-SY5Y cell lysates, and the isolated complex rons with HNE for 3 h and then measured c-secretase activity. Neurons obtained was then incubated with HNE at concentrations that have been exposed to HNE at concentrations of 1–10 lM, which have been previ- reported in various biological tissues (0.1–5 lM). It was found that incuba- ously reported to occur in AD and in experimental models of AD (Mark tion of c-secretase complex with 1 or 2 lM HNE for 30 min significantly et al., 1997; McGrath et al., 2001), exhibited significantly greater c-sec- increased the activity of c-secretase by 30% as compared with vehicle- retase activity than vehicle-treated control neurons (Fig. 1A-C). Iron treated controls, which demonstrated that HNE has a direct effect on (Fe2+), which induces membrane lipid peroxidation and HNE production, c-secretase complex (Fig.
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