Physiological levels of β-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production

Abstract

β-amyloid (Aβ), the major component of senile plaques in Alzheimer's disease (AD), normally circulates in the blood at nanomolar levels but is elevated in AD. Previous studies have found that high concentrations (10-5 -10-4 M) of Aβ result in neuronal cell death. Here we show that physiological levels of soluble Aβ can induce dysfunction in perfused rat cerebral vessels and in cultured endothelial cells. At concentrations of 10-9 -10-6 M, Aβ induced a significant concentration-dependent reduction of NO production in endothelial cells. At 10-8 M, Aβ significantly decreased the sensitivity of cerebral vessels to acetylcholine (ACh), an endothelium dependent vasodilator. At 10-7 M and higher concentrations, Aβ significantly reduced the maximum response of vessels to ACh, and induced significant endothelial cell death. Aβ (10-9 -10-5 M) did not cause any detectable change in nitric oxide synthase levels. The results suggest that a modest increase in the concentration of Aβ above its normal physiological level in the circulation, as found in the early stages of AD, results in decreased NO production and vessel sensitivity to endothelium-dependent vasodilation that could lead to constricted blood vessels and ischemia in the surrounding tissue. Further increases in Aβ concentration, which may occur in the later stages of AD, result in cell death and decreased maximum vasodilator response of cerebral vessels. [Neurol Res 2001; 23: 506-512]