Amyloid β-peptide induces nitric oxide production in rat hippocampus:: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors

Amyloid beta-peptide (Abeta) plays a critical role in the development of Alzheimer's disease. However, the molecular mechanisms of Abeta-induced brain damage in vivo remain to be elucidated. Here, we investigated whether overproduction of nitric oxide (NO) catalyzed by inducible NO synthase (iNOS) is involved in Abeta-induced brain dysfunction. Chronic intracerebroventricular infusion of Abeta1-40 induced iNOS mRNA expression in the hippocampus on days 3 and 5 after the infusion. An accumulation of NO metabolites was observed, and the peak correlated with expression of iNOS mRNA. Measurement of NOS activities revealed an increase in Ca2+-independent, but not Ca2+-dependent, activity. Immunohistochemistry identified numerous iNOS-immunoreactive microglia and astrocytes in the dentate gyrus and to a lesser extent in the CA1 subfield of the hippocampus. Daily treatment with the iNOS inhibitor aminoguanidine (AG, 100 mg/kg/day, i.p.) or S-methylisothiourea (10 mg/kg/day, i.p.) during Abeta infusion prevented an impairment of nicotine-evoked acetylcholine release induced by Abeta, whereas the neuronal NOS inhibitor 7-nitroindazole (30 mg/kg/day, i.p.) had no effect. Daily treatment with AG also ameliorated the impairment of spatial learning of Abeta-infused rats in a radial arm maze. Our findings suggest that overproduction of NO catalyzed by iNOS is responsible for Abeta-induced brain dysfunction.