Insights into Caspase-Mediated Apoptotic Pathways Induced by Amyloid-β in Cerebral Microvascular Endothelial CellsFossati S.a · Ghiso J.a, b · Rostagno A.a
Departments of aPathology and bPsychiatry, New York University School of Medicine, New York, N.Y., USA
Silvia Fossati, PhD
Department of Pathology, New York University School of Medicine
550 First Avenue (MSB-556)
New York, NY 10016 (USA)
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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.
© 2011 S. Karger AG, Basel
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