Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation.
Amyloid beta peptide (A beta), a 39 to 43 amino acid fragment of the beta-amyloid precursor protein (betaAPP), forms insoluble fibrillar accumulation in neurofibrillary tangles and vascular plaques. A beta has been implicated in neuronal and vascular degeneration in brain regions susceptible to plaque formation because of its cytotoxic effect on neurons and endothelial cells (ECs). The authors used a murine cerebral endothelial cell (CEC) line and primary cultures of bovine CECs to explore the cytotoxic mechanism of A beta. A beta 1-40 and A beta 25-35 peptides caused cell death in a dose-dependent and time-dependent manner. Exposure to either A beta 25-35 or A beta 1-40 at 10 micromol/L for 48 hours caused at least 40% cell death. Cerebral endothelial cell death was characterized by nuclear condensation, mitochondrial dysfunction, and nuclear and mitochondrial DNA damage. A beta 25-35 activated both caspase-8 and caspase-3 in murine CECs. zVAD-fmk, a broad-spectrum caspase inhibitor, prevented A beta 25-35-induced increase in caspase-3 activity and CEC death. N-acetyl-cysteine, an antioxidant, also prevented A beta-induced cell death. Together, these findings indicate that A beta-mediated CEC death is an apoptotic process that is characterized by increased oxidative stress, caspase activation, mitochondrial dysfunction, and nuclear and mitochondrial DNA damage.
Xu
J
J
Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, USA.
Chen
S
S
Ku
G
G
Ahmed
S H
SH
Xu
J
J
Chen
H
H
Hsu
C Y
CY
D000111:Acetylcysteine / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000098:blood supply*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002417:Cattle; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004272:DNA, Mitochondrial / Q000032:analysis; D004730:Endothelium, Vascular / Q000201:enzymology / Q000648:ultrastructure*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D020287:In Situ Nick-End Labeling; D051379:Mice; D008928:Mitochondria / Q000502:physiology*
D000590:Amino Acid Chloromethyl Ketones; D016229:Amyloid beta-Peptides; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004272:DNA, Mitochondrial; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000111:Acetylcysteine