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 (beta APP), forms insoluble fibrillar accumulatio n in neurofibrillary tangles and vascular plaques. A beta has been implicat ed in neuronal and vascular degeneration in brain regions susceptible to pl aque formation because of its cytotoxic effect on neurons and endothelial c ells (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-de pendent and time-dependent manner. Exposure to either A beta 25-35 or A bet a 1-40 at 10 mu mol/L for 48 hours caused at least 40% cell death. Cerebral endothelial cell death was characterized by nuclear condensation, mitochon drial dysfunction, and nuclear and mitochondrial DNA damage. A beta 25-35 a ctivated both caspase-8 and caspase-3 in murine CECs. zVAD-fmk, a broad-spe ctrum caspase inhibitor, prevented A beta 25-35-induced increase in caspase -3 activity and CEC death. N-acetyl-cysteine, an antioxidant, also prevente d A beta -induced cell death. Together, these findings indicate that A beta -mediated CEC death is an apoptotic process that is characterized by incre ased oxidative stress, caspase activation, mitochondrial dysfunction, and n uclear and mitochondrial DNA damage.