Extracellular accumulation of beta-amyloid peptides induces apoptosis in cultured neurons via a mechanism independent of unfolded protein responses

Abstract

Extracellular accumulation of beta-amyloid (A ) peptides in senile plaques is one of the pathological hallmarks in Alzheimer’s disease (AD), which can trigger apoptosis. We have previously shown that A triggered calcium release from the ER. Disruption of ER Ca 2+ homeostasis has been suggested to cause 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 A peptides on UPR. In our previous studies, activation of the double-stranded RNA-dependent protein kinase (PKR) has been proved to play important role in A -induced apoptosis. Since UPR can be an upstream effector of PKR, our study aims to investigate whether extracellular accumulation of A peptides induces UPR in cultured neurons. Thapsigargin (Tg) and dithiothreitol (DTT) served as UPR inducers. Our results showed that A could not trigger UPR signalings including phosphorylation of PERK, alternative cleavage of xbp-1 mRNA and induction of transcription of xbp-1 and Gadd153. Using fluorescent imaging, neurons treated with A peptides display granulovacuolar structures in the ER, which implies that autophagy might occur in the ER. Taken together, our results suggest that extracellular accumulation of A peptides induces apoptosis via a mechanism independent of UPR. Acknowledgement: This work is partly supported by HKU Seed Funding for Basic Research (2004–2005), Competitive Earmarked Research Grant award (HKU 7699/05M) from Research Grant Council to RCCC, and PROCORE-France/Hong Kong Joint research Scheme sponsored by Consulate General of France in Hong Kong and Research Grant Council of Hong Kong SAR Government (F-HK21/03T) to R.C.C.C. and J.H.