Pyroglutamate-amyloid-β peptide expression in Drosophila leads to caspase-dependent and endoplasmic reticulum stress-related progressive neurodegeneration.

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. A beta(pE3-42) (an N-terminal-truncated amyloid-beta 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 A beta(1-42). In the present study, we established a Drosophila melanogaster model that expresses A beta(E3Q)(3-42), which effectively produces A beta(pE3-42), and investigated the function of A beta(pE3-42) using the photoreceptor neurons of Drosophila. A beta(pE3-42) 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 A beta(pE3-42). We also confirmed that human Tau-dependent apoptotic induction was strongly enhanced by A beta(pE3-42). Thus, A beta(pE3-42) expression system in the fly may be a promising new tool for studying late-onset neurodegeneration in AD.