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Insights into Caspase-Mediated Apoptotic Pathways Induced by Amyloid-β in Cerebral Microvascular Endothelial Cells

2011; Karger Publishers; Volume: 10; Issue: 1-4 Linguagem: Inglês

10.1159/000332821

1660-2862

Silvia Fossati, Jorge Ghiso, Agueda Rostagno,

Cerebrovascular and genetic disorders

<i>Background:</i> 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. <i>Objective:</i> 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. <i>Methods:</i> We challenged human brain microvascular endothelial cells with both Aβ variants, and studied the apoptotic pathways triggered by these peptides. <i>Results:</i> 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. <i>Conclusion: </i>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.