Transgenic mice overexpressing the amyloid precursor protein (APP) have a profound impairment in endothelium-dependent cerebrovascular responses that is counteracted by the superoxide scavenger superoxide dismutase (SOD). The authors investigated whether the amyloid-beta peptide (A beta) is responsible for the cerebrovascular effects of APP overexpression. Cerebral blood flow (CBF) was monitored by a laser-Doppler flowmeter in anesthetized-ventilated mice equipped with a cranial window. Superfusion of A beta1-40 on the neocortex reduced resting CBF in a dose-dependent fashion (-29% +/- 7% at 5 micromol/L) and attenuated the increase in CBF produced by the endothelium-dependent vasodilators acetylcholine (-41% +/- 8%), bradykinin (-39% +/- 9%), and the calcium ionophore A23187 (-37% +/- 5%). A beta1-40 did not influence the CBF increases produced by the endothelium-independent vasodilators S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, A beta1-42 did not attenuate resting CBF or the CBF increases produced by endothelium-dependent vasodilators. Cerebrovascular effects of A beta1-40 were reversed by the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of methionine 35 with norleucine, a mutation that blocks the ability of A beta to generate reactive oxygen species, abolished A beta1-40 vasoactivity. The authors conclude that A beta1-40, but not A beta1-42, reproduces the cerebrovascular alterations observed in APP transgenics. Thus, A beta1-40 could play a role in the cerebrovascular alterations observed in Alzheimer's dementia.