1. Insights into Caspase-Mediated Apoptotic Pathways Induced by Amyloid-β in Cerebral Microvascular Endothelial Cells
- Author
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Agueda Rostagno, Jorge Ghiso, and Silvia Fossati
- Subjects
Paper ,Time Factors ,Amyloid ,Glutamine ,Glutamic Acid ,Apoptosis ,Mitochondrion ,Microscopy, Electron, Transmission ,medicine ,Humans ,Caspase ,Cell Line, Transformed ,Cerebral Cortex ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,biology ,Cytochrome c ,Endothelial Cells ,Human brain ,medicine.disease ,Peptide Fragments ,Cell biology ,medicine.anatomical_structure ,Neurology ,Cell culture ,Caspases ,Microvessels ,Mutation ,Immunology ,biology.protein ,Neurology (clinical) ,Cerebral amyloid angiopathy ,Signal Transduction - 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-β (Aβ) 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 Aβ40 or its vasculotropic E22Q variant. Methods: We challenged human brain microvascular endothelial cells with both Aβ 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 Aβ oligomers/protofibrils in vascular cells, likely implicating a primary activation of death receptors.
- Published
- 2011