Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells.
Oxidative stress is associated with beta-amyloid peptide (A beta) accumulation in the brains of Alzheimer's disease patients. A beta is generated upon the sequential proteolytic cleavage of transmembrane amyloid precursor protein (APP) by two membrane-bound proteases, beta-secretase (BACE1) and the gamma-secretase complex comprising presenilin 1 (PS1), nicastrin, APH-1 and PEN-2. Recent evidence suggests that significant amounts of BACE1 and gamma-secretase components localize in the cholesterol-rich region of membranes known as lipid rafts, where A beta production occurs preferentially. In this study, we investigated the effects of oxidative stress on the BACE1 and gamma-secretase components in lipid rafts using human neuroblastoma SH-SY5Y cells exposed to ethacrynic acid (EA), a compound that induces cellular glutathione depletion. Following exposure of cells to EA, heme oxygenase-1, a marker protein of oxidative stress, was strongly induced. Moreover, treatment with EA resulted in a significant increase in PS1 protein levels, but not those of nicastrin, APH-1, PEN-2 or BACE1, in both cell lysates and the lipid raft fraction. This increase in PS1 protein expression was prevented by co-treatment with an antioxidant, N-acetylcysteine (NAC). EA additionally induced a significant increase in PS1 mRNA expression, which was inhibited by NAC. Finally, EA treatment was found to promote A beta secretion from cells expressing Swedish mutant APP. It appears that in our cell culture model, oxidative stress enhances PS1 protein levels in lipid rafts via up-regulation of PS1 transcription, which may constitute the mechanism underlying the oxidative stress-associated promotion of A beta production.
Oda
Akiko
A
Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Tokyo, Japan.
Tamaoka
Akira
A
Araki
Wataru
W
D000111:Acetylcysteine / Q000494:pharmacology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D004976:Ethacrynic Acid / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D053764:Presenilin-1; D012333:RNA, Messenger; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D053829:Amyloid Precursor Protein Secretases; D005978:Glutathione; D004976:Ethacrynic Acid; D000111:Acetylcysteine