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Abstract

Several species of beta-amyloid peptides (Abeta) exist as a result of differential cleavage from amyloid precursor protein (APP) to yield various C-terminal Abeta peptides. Several N-terminal modified Abeta peptides have also been identified in Alzheimer's disease (AD) brains, the most common of which is pyroglutamate-modified Abeta (AbetapE3-42). AbetapE3-42 peptide has an increased propensity to aggregate, appears to accumulate in the brain before the appearance of clinical symptoms of AD, and precedes Abeta1-42 deposition. Moreover, in vitro studies have shown that AbetapE3-42 can act as a seed for full length Abeta1-42. In this study, we characterized the Drosophila model of AbetapE3-42 toxicity by expressing the peptide in specific sets of neurons using the GAL4-UAS system, and measuring different phenotypic outcomes. We found that AbetapE3-42 peptide had an increased propensity to aggregate. Expression of AbetapE3-42 in the neurons of adult flies led to behavioural dysfunction and shortened lifespan. Expression of AbetapE3-42 constitutively in the eyes led to disorganised ommatidia, and activation of the c-Jun N-terminal kinase (JNK) signaling pathway. The eye disruption was almost completely rescued by co-expressing a candidate Abeta degrading enzyme, neprilysin2. Furthermore, we found that neprilysin2 was capable of degrading AbetapE3-42. Also, we tested the seeding hypothesis for AbetapE3-42 in vivo, and measured its effect on Abeta1-42 levels. We found that Abeta1-42 levels were significantly increased when Abeta1-42 and AbetapE3-42 peptides were co-expressed. Furthermore, we found that AbetapE3-42 enhanced Abeta1-42 toxicity in vivo. Our findings implicate AbetapE3-42 as an important source of toxicity in AD, and suggest that its specific degradation could be therapeutic.