Caspase-8 activation and oxidative stress are involved in the cytotoxic effect of beta-amyloid on rat brain microvascular endothelial cells

Several studies have demonstrated that cerebrovascular dysfunction and damage play a significant role in the pathogenesis of Alzheimer disease (AD). In fact, beta-amyloid peptides (A beta s), the major component of the senile plaques and cerebrovascular amyloid deposits in AD, were shown to be cytotoxic to endothelial cells. We have recently observed that A beta s exert a toxic effect on neuromicrovascular endothelial cells (NECs) in a time- and concentration-dependent manner, apoptosis playing a pivotal role in this process. Hence, it seemed worthwhile to investigate the A beta-mediated apoptosis mechanism in NECs. A beta s were found to induce, after a short incubation period, apoptosis throughout caspase-8 activation. Moreover, A beta s elicited a highly significant (p < 0.001) increase in superoxide dismutase (SOD) levels after a 3-h exposure period, while SOD concentration was not affected after a 24-h incubation. The time-dependent increase in SOD concentration is probably correlated with the production of all excess of reactive oxygen species. Collectively, our findings allow Lis to conclude that: i) A beta s may induce apoptosis via the activation of caspase-8, presumably by cross-linking and activating receptors of the death-receptor family; ii) oxidative stress is possibly involved in the A beta-induced cytotoxic effect; and iii) these two mechanisms do not act sequentially but, probably, are independent of each other.