Production of neurotoxic factors by brain endothelium in Alzheimer's disease.
The cerebral vasculature is central to the maintenance of the neuronal microenvironment. We have previously demonstrated that brain microvessels in Alzheimer's disease produce high, potentially toxic, levels of nitric oxide. It is our hypothesis that neuronal injury in Alzheimer's disease occurs because an abnormal endothelium secretes factors that are toxic to neurons. In this study, we report that inhibition of protein kinase C in endothelial cells causes release of a factor that is toxic to neurons in vitro. Our results demonstrate that this endothelium-derived toxic factor is soluble, heat-labile, susceptible to proteolysis, and loses activity with repeated freeze-thawing. The molecular weight of this putative protein is between 10 and 50 kDa, and 8 hours are required after protein kinase C inhibition to detect the endothelium-derived toxic factor in the media. Finally, the endothelium-derived toxic factor kills neurons within 2 hours, suggesting that cell death occurs via necrosis, not apoptosis. These data support the notion that endothelial cells can create an injurious microenvironment for neurons by producing molecules with noxious properties. Altered/dysfunctional endothelial cells in the cerebral microcirculation could be a novel, unexplored source of neurotoxic factors in Alzheimer's disease.
Grammas
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Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA. paula-grammas@uokhsc.edu
Botchlet
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Moore
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Weigel
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D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008833:Microcirculation; D008970:Molecular Weight; D009410:Nerve Degeneration; D009474:Neurons / Q000166:cytology; D009498:Neurotoxins / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats
D009498:Neurotoxins; D011493:Protein Kinase C