Fadd (fas-associated death domain-containing protein) as a mediator of cell cycle dysregulation in beta-amyloid peptide-induced apoptosis?

Abstract

One of the pathological hallmarks of Alzheimer’s disease (AD) is the senile plaques, which are the extracellular accumulation of beta-amyloid (Aβ) peptides, found in cortex and hippocampus. Neuronal apoptosis has been implicated in AD pathogenesis. In vitro studies have shown that Aβ peptides can induce apoptosis. Owing to the finding of early caspase-8 activation (Suen et al, 2003), as well as our recent publication that extracellular Aβ peptide-triggered apoptosis is independent of the unfolded protein responses (Yu et al, 2006), we proposed the involvement of death receptor signaling in Aβ-induced apoptosis. In the classical death receptor signaling pathway, ligands binding to the death receptor such as Fas-receptor or tumor necrosis factor receptor (TNFR) lead to activation of caspase-8 and caspase-3, which resulted in apoptosis. Fas-Associated Death Domain-containing protein (FADD) is an adaptor molecule that bridges the Fas-receptor to the procaspase-8, thus, forming the death inducing signaling complex (DISC) during apoptosis. To investigate the effects of Aβ toxicity on FADD pathway, we firstly examined the change of both phospho-FADD and FADD proteins during apoptosis. By western blot analysis, the level of phospho-FADD was decreasing when treating with Aβ peptides while FADD protein remained unchanged. To our surprise, immunocytochemical staining showed that both phospho-FADD and FADD reside predominantly in nuclei. Previous studies in cancer research suggest that phospho-FADD plays a role in cell cycle regulation. Together with the recent findings of dysregulation of cell cycle events in postmortem AD brains, we investigate whether phospho-FADD affects the cell cycle regulation which may result in neuronal apoptosis under the Aβ neurotoxicity.