Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Correspondence: Dr. Chung Y. Hsu, Department of Neurology Washington University, School of Medicine Box 8111, 660 S. Euclid Ave. St. Louis, MO 63110, U.S.A.

Received 20 November 2001; Revised 5 February 2001; Accepted 5 February 2001.

Abstract

Amyloid peptide (A), a 39 to 43 amino acid fragment of the -amyloid precursor protein (APP), forms insoluble fibrillar accumulation in neurofibrillary tangles and vascular plaques. A 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. A 1–40 and A 25–35 peptides caused cell death in a dose-dependent and time-dependent manner. Exposure to either A 25–35 or A 1–40 at 10 mol/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 25–35 activated both caspase-8 and caspase-3 in murine CECs. zVAD-fmk, a broad-spectrum caspase inhibitor, prevented A 25–35-induced increase in caspase-3 activity and CEC death. N-acetyl-cysteine, an antioxidant, also prevented A-induced cell death. Together, these findings indicate that A-mediated CEC death is an apoptotic process that is characterized by increased oxidative stress, caspase activation, mitochondrial dysfunction, and nuclear and mitochondrial DNA damage.