Caspase-8 Mediates Amyloid-β-induced Apoptosis in Differentiated PC12 Cells

Abstract

The pathogenesis of Alzheimer's disease (AD) is very complex and there are currently no significant treatments for the disease. Caspase-8 is known to be involved in neuronal apoptosis. To explore a possible molecular mechanisms involved in AD pathology, this study investigated the effect of caspase-8 knockdown on amyloid-β 1-40 (Aβ1-40)-induced apoptosis in PC12 cells. The proliferation of PC12 cells was significantly inhibited in Aβ-treated cells, and a high fraction of the cells underwent apoptosis in a dose- and time-dependent manner. Transfection of caspase-8 small interfering RNA (siRNA) resulted in reduced apoptosis following Aβ1-40 treatment. The activation of caspase-3, caspase-8, and caspase-9 was stimulated by Aβ1-40, an effect that was also significantly reduced by caspase-8 siRNA. Knockdown of caspase-8 increased the phosphorylation of the signaling molecules AKT and ERK1/2 relative to cells treated with Aβ1-40 alone. Caspase-8 is an important effector molecule involved in apoptosis induced by Aβ1-40 and is likely involved in AD pathology. This study suggests that targeted inhibition of caspase-8 may be a new therapeutic for preventing neuronal apoptosis and inhibiting the progression of AD.

Limited activation of the intrinsic apoptotic pathway plays a main role in amyloid-β-induced apoptosis without eliciting the activation of the extrinsic apoptotic pathway

“…A number of studies have indicated that EAPW plays a crucial role in the apoptotic process induced by Aβ42 (13,14,44). In the present study, we observed activation of caspase-8 and Bid processing (Fig.…”

“…Some studies have indicated that EAPW is elicited in Aβ-treated cells (12,44). This conclusion is usually based on activation of caspase-8, cleavage of Bid, upregulation of related proteins, and downregulation of EAPW-inhibiting proteins in the cells.…”

Salidroside protects PC12 cells from Aβ1–40-induced cytotoxicity by regulating the nicotinamide phosphoribosyltransferase signaling pathway

“…The neuronal toxicity of Aβ 1–40 is reflected in its ability to cause energy dysmetabolism, and induce cell damage and death (27,28). A number of previous studies used PC12 cells to investigate the molecular mechanisms underlying the development of degenerative diseases of the nervous system (29–32). Therefore, the present study employed the PC12 cells that were damaged by Aβ 1–40 exposure as the cell model of AD and the significance of NAMPT in AD was evaluated.…”

Components of Goutengsan in Rat Plasma by Microdialysis Sampling and Its Protection on Aβ1–42‐Induced PC12 Cells Injury

“…Some soluble A β oligomers, highly prone to aggregation and self-assemble to form a heterogeneous mixture of oligomers and protofibrils, are considered as the major neurotoxic species in AD [20–22]. A β induced apoptosis occurs in the AD brain and plays a role in neuronal dysfunction and neurodegeneration, which contributes to the progression of AD [23]. In this study, A β 1–42 exposed PC12 cells were used to investigate the protection mechanism of Goutengsan in vitro and rats lateral cerebral ventricle injected with A β 1–42 was used in vivo .…”

“…Executioner caspases (caspase-3, caspase-6, and caspase-7) and upstream effector caspases (caspase-2, caspase-8, caspase-9, and caspase-10) are well known as mediators in AD brains [23]. Caspase-3 and caspase-9 may also be potential therapeutic targets for AD [17].…”