期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 21, 期 6, 页码 702-710出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00004647-200106000-00008
关键词
Alzheimer's disease; apoptosis; cell death; mitochondrial DNA; oxidative stress
资金
- NINDS NIH HHS [NS25545, NS40525, NS28995] Funding Source: Medline
Amyloid beta peptide (A beta), a 39 to 43 amino acid fragment of the beta -amyloid precursor protein (beta APP), 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 mu 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 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.
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