Cerebral blood flow (CBF) is reduced in patients with Alzheimer’s disease (AD), anticipates the development of dementia and correlates inversely with cognitive performance.1 Multiple processes probably contribute to the reduced CBF. Aβ40-mediated up-regulation of reactive oxygen species production by NADPH oxidase has been shown to cause cerebral vasoconstriction,2 and we have shown an intracerebral increase in the potent vasoconstrictor ET-1,3 associated with Aβ42-mediated upregulation of endothelial converting enzyme (ECE)-2.4 We have now examined the relationship between Aβ exposure, oxidative stress and ET-1 release in the cerebral vasculature. We measured ECE-1 activity and ET-1 level in leptomeningeal vessels that had been dissected from the occipital lobe of 20 AD, 17 vascular dementia (VaD) and 20 age-matched normal human control brains provided by the South West Dementia Brain Bank, University of Bristol. We also measured ET-1 release by human cerebrovascular endothelial cells in response to 24h exposure to Aβ or the nitric oxide donor DETA NONOate. In further experiments ET-1 release was measured in response to a combination of the antioxidant superoxide dismutase (SOD) and Aβ40, or SOD alone. ECE-1 activity and ET-1 level correlated closely, and both were significantly elevated in leptomeningeal blood vessels from AD but not VaD brains. Exposure of endothelial cells to 10µM Aβ40 or 5mM DETA NONOate significantly increased the amount of ET-1 in the culture medium. Aβ40-induced release of ET-1 by endothelial cells was prevented by the addition of 1KU SOD. The findings from this and our previous studies indicate that Aβ stimulates ET-1 production in AD: Aβ40 increases microvascular ECE-1 activity in AD, an increase at least partly mediated by oxidative stress, and Aβ42 up-regulates neuronal ECE-2. Both processes lead to the production and release of ET-1. Through its vasoconstrictive action, the elevated level of ET-1 is likely to contribute to the abnormal reduction in CBF in AD. This may be amenable to pharmacological reversal through the use of drugs that block ET-A receptors.