Cerebrovasculature-mediated neuronal cell death.

The presence of significant vascular disease in patients with Alzheimer's disease (AD) and the recognition of the ApoE genotype as a risk factor for both coronary disease and AD support an association between AD and vascular disease. It is our hypothesis that brain microvessels contribute to the pathogenesis of AD by producing soluble factors that injure or kill neurons. In this study we report that AD microvessels produce factors that are noxious to neurons and that these vessels can evoke neuronal cell death in vitro. In these experiments, microvessels are isolated from the cerebral cortices of AD patients and non-demented elderly and young controls. Microvessels isolated from AD brains produce high levels of a known neurotoxin nitric oxide, compared to vessels from aged-matched controls. In addition, we demonstrate a direct neurotoxic effect of AD microvessels when co-cultured with primary rat cerebral cortical neurons. In contrast, vessels from elderly non-demented donors are less lethal, and brain vessels from younger donors are not neurotoxic. Similarly, AD vessels exhibit a dose-dependent toxicity in co-culture with the human neurons. Finally, treatment of AD microvessels with the protein synthesis inhibitor cycloheximide reduces AD vessel neurotoxicity, suggesting that the neurotoxic factor is a protein. These findings suggest that the cerebral microvasculature is a source of factors that can injure neurons and implicate a novel mechanism of vascular-mediated neuronal cell death in AD.