Amyloid β‐peptide (Aβ) plays a critical role in the development of Alzheimer's disease. However, the molecular mechanisms of Aβ‐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 Aβ‐induced brain dysfunction. Chronic intracerebroventricular infusion of Aβ1‐40 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 Aβ infusion prevented an impairment of nicotine‐evoked acetylcholine release induced by Aβ, 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 Aβ‐infused rats in a radial arm maze. Our findings suggest that overproduction of NO catalyzed by iNOS is responsible for Aβ‐induced brain dysfunction.
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