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

Abstract

Several studies have demonstrated that cerebrovascular dysfunction and damage play a significant role in the pathogenesis of Alzheimer disease (AD). In fact, ß-amyloid peptides (Aßs), 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 Aßs 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 Aß-mediated apoptosis mechanism in NECs. Aßs were found to induce, after a short incubation period, apoptosis throughout caspase-8 activation. Moreover, Aßs 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) Aßs 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 Aß-induced cytotoxic effect; and iii) these two mechanisms do not act sequentially but, probably, are independent of each other.

Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid‐β variants in cells composing the cerebral vessel walls

“…The additional participation of caspase-8, suggested by the protective effect achieved by its specific inhibitor, indicates an additional participation of receptor-mediated pathways, as also suggested for nonhuman ECs challenged with a nonphysiologic A␤-truncated fragment (34). The present data indicate the A␤-mediated induction of analogous cell-death mechanisms in vascular cells as those described in neurons in which, in addition to an active mitochondrial participation (33,35), apoptotic mechanisms engaging cell-death receptors have also been postulated (36). Whether in our experimental design both intrinsic and extrinsic pathways are simultaneously activated or the mitochondrial dysfunction is a mere result of a primary involvement of cell-death receptors is currently being elucidated.…”

“…Active forms of effector caspases were found colocalizing with neurofibrillary tangles, senile plaques, and dystrophic neurites (33, 37), while mRNA evaluation corroborated the up-regulation in the AD temporal cortex of caspase-3 and caspase-7, as well as of the death receptor-related caspase-8 (38), in agreement with our own findings in cerebrovascular cells. Whether independently initiated or triggered through caspase-8 activation, the mitochondrial apoptosis pathway seems to have active participation in AD and other neurodegenerative disorders (33,35,36). Many of the apoptosis-associated genes transcriptionally up-regulated in AD are active participants in the mitochondrial cascade, e.g., elevated levels of Bax and Bak coexist with down-regulated expression of the antiapoptotic Bcl-2 family members in the brains of affected individuals (33,39).…”

Protection of the Blood-Brain Barrier by Pentosan Against Amyloid-β-Induced Toxicity

“…The toxic effect of the Dutch Aβ peptides on BBB is further supported by an in vivo study showing that these mutant peptides are not cleared from CSF [53]. The Akt [54], and protein kinase C [55] signalling pathways, the RAGE [56] and the activation of caspase-8 [57] can participate in the decrease of cell viability and apoptotic cascade induced by Aβ in endothelial cells.…”

Amyloid β peptide toxicity in differentiated PC12 cells: Calpain‐calpastatin, caspase, and membrane damage

“…Caspase‐8 inhibition prevented Aβ‐induced death of cultured hippocampal neurons but did not prevent staurosporine‐induced toxicity (Ivins et al, 1999). Caspase‐8 was also shown to be involved in Aβ‐induced toxicity in the neuronal cell line SHSY5Y (Cantarella et al, 2003) and in brain microvascular endothelial cells (Folin et al, 2006).…”