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

Fossati S.a · Ghiso J.a, b · Rostagno A.a

Author affiliations

Departments of aPathology and bPsychiatry, New York University School of Medicine, New York, N.Y., USA

Corresponding Author

Silvia Fossati, PhD

Department of Pathology, New York University School of Medicine

550 First Avenue (MSB-556)

New York, NY 10016 (USA)

Tel. +1 212 263 7724, E-Mail silvia.fossati@nyumc.org

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Neurodegenerative Dis 2012;10:324–328

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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.

© 2011 S. Karger AG, Basel


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Article / Publication Details

First-Page Preview
Abstract of Paper

Received: June 30, 2011
Accepted: September 02, 2011
Published online: December 07, 2011
Issue release date: April 2012

Number of Print Pages: 5
Number of Figures: 2
Number of Tables: 0

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: https://www.karger.com/NDD


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