Transgenic mice (Tg2576) that express the Swedish double mutation of human amyloid precursor protein and develop Alzheimer-like beta-amyloid deposits in the aged brain, were used to study the effect of beta-amyloid deposition on expression of both neuronal (nNOS) and inducible nitric oxide synthase (iNOS) in cells surrounding beta-amyloid plaques. Nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry and double immunofluorescent labeling revealed that most of the fibrillary, thioflavine-S-positive cortical beta-amyloid deposits in 13-, 17-, and 21-month-old transgenic animals were closely associated with dystrophic nNOS-positive neurons, while nNOS-bearing neurons located more distal to plaques appeared to be unaffected. There was no significant expression of iNOS in transgenic mouse brain. The data suggest enhanced vulnerability of nNOS-containing neocortical neurons to beta-amyloid toxicity. Alternatively, expression of nNOS may also be a response to plaque-mediated damage of neurons, consistent with a neuroprotective role of nitric oxide.