Vascular inflammatory, oxidative and protease-based processes: implications for neuronal cell death in Alzheimer's disease.
A substantial literature demonstrates activation of inflammatory processes in the Alzheimer's disease (AD) brain and an association between inflammation and oxidative stress. We have shown that brain microvessels from AD patients express high levels of inflammatory proteins and that these proteins evoke release of the neurotoxic protease thrombin from brain endothelial cells. The objective of this study was to determine the effects of inflammatory proteins on brain endothelial cell reactive oxygen species generation, protease release and cell apoptosis. Also, the effects of inflammatory proteins on neuronal reactive oxygen species generation, injury and apoptosis were assessed. Treatment of cultured brain endothelial cells with inflammatory proteins (LPS, IL-1beta, IL-6, IFN-gamma, TNF-alpha) resulted in a significant increase (p < 0.01) in intracellular levels of reactive oxygen species by 1 h. Inflammatory proteins also caused release of tissue plasminogen activator and increased apoptosis by 24 h in these cells. In cultured neurons, inflammatory proteins caused an increase in reactive oxygen species, membrane fluidity, and apoptosis by 24 h, as detected by fluorescent microscopy. Taken together, these data support the hypothesis that vascular inflammatory, oxidative and protease-based processes contribute to neuronal cell death, and suggest that therapies targeted at these mediators and processes could be effective in AD.
Christov
Alexander
A
Department of Pathology and the Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Ottman
J Todd
JT
Grammas
Paula
P
D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D002561:Cerebrovascular Disorders / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010447:Peptide Hydrolases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D010447:Peptide Hydrolases; D013917:Thrombin; D010959:Tissue Plasminogen Activator