Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. During the progression of AD, massive neuronal degeneration occurs in the late stage of the disease; however, the molecular mechanisms responsible for this neuronal loss remain unknown. AβpE3-42 (an N-terminal-truncated amyloid-β peptide that begins with pyroglutamate at the third position) is produced during late-stage AD. It also aggregates more rapidly in vitro and exhibits greater toxicity in neurons than full-length Aβ1-42. In the present study, we established a Drosophila melanogaster model that expresses Aβ3-42E3Q, which effectively produces AβpE3-42, and investigated the function of AβpE3-42 using the photoreceptor neurons of Drosophila. AβpE3-42 induced caspase-dependent apoptosis and caused progressive degeneration in photoreceptor neurons. Mutations in ER stress response genes or the administration of an inhibitor of the ER stress response markedly suppressed the degeneration phenotype, suggesting that the ER stress response plays an important role in neurodegeneration caused by AβpE3-42. We also confirmed that human Tau-dependent apoptotic induction was strongly enhanced by AβpE3-42. Thus, AβpE3-42 expression system in the fly may be a promising new tool for studying late-onset neurodegeneration in AD.