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

beta -amyloid (A beta), 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 A beta result in neuronal cell death. Here we show that phy siological levels of soluble A beta fan induce dysfunction in: perfused rat cerebral vessels and in cultured endothelial cells. At concentrations of 1 0(-9)-10(-6) M, A beta induced a significant concentration-dependent reduct ion of NO production in endothelial cells. At 10(-8) M, A beta significantl y decreased the sensitivity of cerebral vessels to acetylcholine (ACh), an endothelium dependent vasodilator. At 10(-7) M and higher concentrations, A beta significantly reduced the maximum response of vessels to ACh, and ind uced significant endothelial cell death. A beta (10(-9)-10(-5) M): did nor cause any detectable change in nitric oxide synthase levels. The results su ggest that a modest increase in the concentration of A beta above its norma l physiological level in the circulation, as found in the early stages of A beta, results in decreased NO production and Vessel sensitivity to endothe lium dependent vasodilation that could lead to constricted blood vessels an d ischemia in the surrounding tissue. Further increases in A beta concentra tion, which may occur in the later stages of AD, result in cell death and d ecreased maximum vasodilator response of cerebral vessels.