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 (Abetas), 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 Abetas 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 Abeta-mediated apoptosis mechanism in NECs. Abetas were found to induce, after a short incubation period, apoptosis throughout caspase-8 activation. Moreover, Abetas 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 an excess of reactive oxygen species. Collectively, our findings allow us to conclude that: i) Abetas 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 Abeta-induced cytotoxic effect; and iii) these two mechanisms do not act sequentially but, probably, are independent of each other.
Folin
Marcella
M
Department of Biology, University of Padua, Italy. folin@civ.bio.unipd.it
Baiguera
Silvia
S
Fioravanzo
Lara
L
Conconi
Maria Teresa
MT
Grandi
Claudio
C
Nussdorfer
Gastone G
GG
Parnigotto
Pier Paolo
PP
D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D008165:Luminol; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D008165:Luminol; D013482:Superoxide Dismutase; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases