Abstract T P243: Death Receptors and Mitochondria as Crucial Targets for Drug Discovery in Cerebral Amyloid Angiopathy
The vascular deposition of amyloid, known as Cerebral Amyloid Angiopathy (CAA) is an age-associated condition featured in about 90% of Alzheimer’s disease cases and in the aging brain. Amyloid beta (Abeta) deposition in CAA compromises cerebral blood flow and can cause cerebral hemorrhage and cognitive impairment, by mechanisms that are still poorly understood. Our goal was to identify the molecular events underlying the apoptotic cascade generated by Abeta in cerebrovascular cells and to pinpoint new targets for drug discovery. Human brain microvascular endothelial cells were challenged with vasculotropic Abeta variants associated with cerebrovascular deposition and hemorrhagic outcome, and the resulting signaling pathways were analysed. The in vitro findings were validated in vivo in mice subjected to intrahippocampal Abeta injections and confirmed in human CAA cases. Our findings highlighted an activation of caspase-8 and -9, together with mitochondrial dysfunction and release of cytochrome C, suggesting death receptor mediated apoptosis, which was confirmed by an overexpression of the TRAIL (TNF-related apoptosis inducing ligand) death receptors DR4 and DR5. Signaling cascades typical of TRAIL death receptor-mediated pathways were activated. The same receptors colocalized with Abeta on the cell membrane after amyloid challenge, and immunoprecipitated in vitro with Abeta oligomers. SiRNAs against DR4 and DR5 and the prevention of mitochondrial dysfunction through Carbonic Anhydrase Inhibitors, significantly diminished Abeta mediated apoptosis in endothelial cells. In vivo experiments in mice injected with vasculotropic Abeta peptide and in human CAA cases confirmed the upregulation of the receptors, their colocalization with Abeta on the cerebral vasculature, and the activation of caspases, which could be prevented by carbonic anhydrase inhibitors. Our data strongly suggests that TRAIL death-receptors and mitochondrial functioning are key cellular targets for therapeutic intervention against Abeta-induced vascular cell death in CAA.
Author Disclosures: S. Fossati: None. P. Giannoni: None. M. Solesio: None. M. Hernandez: None. J. Ghiso: None. A. Rostagno: None.
This research has received full or partial funding support from the American Heart Association, Founders - Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont.
- © 2015 by American Heart Association, Inc.