β-Amyloid peptide-induced neuronal apoptosis is independent of unfolded protein responses

Abstract

Accumulation of beta-amyloid (Aβ) peptides in senile plaques is one of the pathological hallmarks in Alzheimer’s disease (AD). Neuronal apoptosis has been implicated in AD pathogenesis. Ours and other laboratories have demonstrated that Aβ peptides triggered Ca2+ release from the endoplasmic reticulum (ER). Disruption of Ca2+ homeostasis has been considered to lead to the unfolded protein responses (UPR). While hypothesis has been made about UPR and neurodegeneration in AD, little is known about the effects of extracellular accumulation of Aβ peptides on UPR. Our previous studies showed that activation of the double-stranded RNA-dependent protein kinase (PKR) pathway participates in Aβ-triggered apoptosis. Since UPR can be an upstream event of PKR, this study aimed to elucidate whether extracellular accumulation of Aβ peptides induce UPR in cultured neurons. Thapsigargin (Tg) and dithiothreitol (DTT) served as UPR inducers. Our results showed that Aβ peptides could not trigger UPR signaling including phosphorylation of PKR-like ER resident kinase, alternative cleavage of xbp-1 and increased gene expression of xbp-1 and gadd153. However, Aβ peptides activated caspase-7 and caspase-9. Using fluorescent imaging, we found that neurons treated with Tg or DTT displayed rod-shape ER structures, while neurons treated with Aβ showed granulovacuolar structures in the ER, which suggested that autophagy might occur in the ER. Taken together, our results suggested that extracellular accumulation of Aβ peptides induce apoptosis via a mechanism independent of UPR. Supported by This work is partly supported by HKU Seed Funding for Basic Research (2004-2005) to RCCC, and PROCORE-France/Hong Kong Joint research Scheme (F-HK21/03T) to RCCC and JH.