Accumulation of beta-amyloid (Aβ) peptides in senile plaques is one of the pathological hallmarks in Alzheimer's disease (AD), which can trigger apoptosis. We have previously demonstrated that Aβ triggered calcium release from the ER. Depletion of ER Ca2+ ions has been reported leading to 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 on UPR. We have shown previously that activation of PKR in Aβ-triggered apoptosis. Since UPR can trigger PKR, our study aims to elucidate whether extracellular accumulation of Aβ peptides induce UPR in cultured neurons. Our results showed that Aβ could not trigger UPR signalings including phosphorylation of PERK, alternative cleavage of xbp-1 mRNA and induction of transcription of xbp-1 and Gadd153. Taken together, our results suggest that extracellular accumulation of Aβ peptides induce apoptosis via a mechanism independent of UPR.