Presenilin-1-deficient neurons are nitric oxide-dependently killed by hydrogen peroxide in vitro.
Presenilin-1 (PS1) is the gene responsible for the development of early-onset familial Alzheimer's disease. To probe the functions of PS1 on neuronal resistance to oxidative stress, we pharmacologically examined the death signals in PS1-deficient neurons induced by oxidative stress. Because the death of primarily cultured neurons lacking PS1 is caused by hydrogen peroxide in calcium-dependent manners in vitro [J Neurochem 78 (2001) 807], we tested the neuronal survival-promoting ability of inhibitors against calcium-dependent/cell death-related signaling molecules, such as ERKs, JNK, p38 MAP kinase, calcineurin, calpain, and nitric oxide synthase (NOS). All inhibitors tested failed to rescue the PS1-deficient neurons from the death with the exception of an inhibitor of NOS, N(G)-nitro-l-arginine methyl ester. Hemoglobin, a nitric oxide (NO) scavenger, also prevented the death of the mutant neurons. NADPH-diaphorase staining, which accounts for NOS activity, was enhanced in the mutant neurons. These results suggest that PS1 has a role for NOS activation in neurons and confers oxidative stress-resistance on neurons in calcium/NO-dependent manners.
Nakajima
M
M
Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan.
Shirasawa
T
T
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006454:Hemoglobins / Q000378:metabolism / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000235:genetics; D053764:Presenilin-1
D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006454:Hemoglobins; D008565:Membrane Proteins; D016877:Oxidants; D053764:Presenilin-1; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D009252:NADPH Dehydrogenase; D019331:NG-Nitroarginine Methyl Ester