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.