A damaged microcirculation contributes to neuronal cell death in Alzheimer's disease.

Alzheimer's disease (AD) involves multiple etiologic factors and a complex pathogenesis. Vascular factors are increasingly implicated in the pathogenesis of AD. In this paper we review evidence that AD brain microvessels are biochemically altered and contribute to neuronal injury and death by release of factors directly injurious to neurons. Our data show that when brain microvessels are "injured" by anoxia they produce high levels of reactive oxygen species. Comparisons of isolated brain microvessels from AD and age-matched controls show specific abnormalities in alpha(1) and beta receptors and in protein kinase C and protein kinase A signaling pathways. In AD but not in controls, the cerebral microcirculation expresses the inflammatory mediator CAP37 and over produces nitric oxide. Finally, we demonstrate that AD microvessels secrete toxic factors that cause neuronal cell death in vitro. These latter experiments showing that AD brain microvessels, in co-culture or vessel-conditioned media, cause lethal injury to neurons in culture, establish a direct link between endothelial cell products and neuronal cell death in this disease.