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Neurodegenerative Diseases 2012, Vol. 10 (1-4) :324 -328 doi:10.1159/000332821 <<-上一篇 下一篇 ->>
Insights into Caspase-Mediated Apoptotic Pathways Induced by;Amyloid-beta in Cerebral Microvascular Endothelial Cells
Fossati, Silvia;Ghiso, Jorge;Rostagno, Agueda
[Fossati, Silvia; Ghiso, Jorge; Rostagno, Agueda] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA.;[Ghiso, Jorge] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA.
Abstract: Background: The vascular deposition of amyloid known as cerebral amyloid angiopathy (CAA) - an age-associated condition and a common finding in Alzheimer's disease - compromises cerebral blood flow, causing macro/microhemorrhages and/or cognitive impairment. Very little is known about the mechanisms causing CAA-related degeneration of cerebral vascular cells. The Dutch E22Q familial amyloid-beta (A beta) variant is primarily associated with CAA, and manifests clinically with severe cerebral hemorrhages. Objective: We aimed to determine the molecular mechanisms causing apoptosis of cerebral endothelial cells in the presence of wild-type A beta 40 or its vasculotropic E22Q variant. Methods: We challenged human brain microvascular endothelial cells with both A beta variants, and studied the apoptotic pathways triggered by these peptides. Results: Caspase-mediated apoptotic pathways were elicited by both peptides within time frames correlating with their aggregation properties and formation of oligomeric/protofibrillar assemblies. Our data revealed a primary activation of caspase-8 (typically triggered by death receptors) with secondary engagement of caspase-9, with cytochrome C and apoptosis-inducing factor release from the mitochondria, suggesting the independent or synergistic engagement of extrinsic and intrinsic apoptotic mechanisms. Conclusion: Our data demonstrate the induction of caspase-8- and caspase-9-dependent mitochondrial-mediated apoptotic pathways by A beta oligomers/protofibrils in vascular cells, likely implicating a primary activation of death receptors. Copyright (C) 2011 S. Karger AG, Basel
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